CHRFAM7A

Chr 15

CHRNA7 (exons 5-10) and FAM7A (exons A-E) fusion

Also known as: CHRNA7, CHRNA7-DR1, D-10

NCBI Gene: 89832 ENSG00000166664 UniProt: Q494W8 OMIM: 609756

The protein product of this hybrid gene would form a truncated nicotinic acetylcholine receptor subunit that lacks most of the neurotransmitter binding domain but retains the transmembrane ion channel region, though translation of functional protein has not been confirmed. This gene is extremely tolerant to loss-of-function mutations based on population genetics data (very low pLI score), and no established Mendelian diseases have been linked to CHRFAM7A mutations. The gene represents a partial duplication of CHRNA7 located in a chromosomal region associated with neuropsychiatric disorders.

OMIM ResearchSummary from RefSeq

The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The family member CHRNA7, which is located on chromosome 15 in a region associated with several neuropsychiatric disorders, is partially duplicated and forms a hybrid with a novel gene from the family with sequence similarity 7 (FAM7A). Alternative splicing has been observed, and two variants exist, for this hybrid gene. The N-terminally truncated products predicted by the largest open reading frames for each variant would lack the majority of the neurotransmitter-gated ion-channel ligand binding domain but retain the transmembrane region that forms the ion channel. Although current evidence supports transcription of this hybrid gene, translation of the nicotinic acetylcholine receptor-like protein-encoding open reading frames has not been confirmed. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.22

Clinical Summary— CHRFAM7A

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

41 VUS of 47 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.22LOEUF

pLI 0.000

Z-score 1.06

OE 0.65 (0.37–1.22)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.59Z-score

OE missense 0.85 (0.73–1.00)

108 obs / 126.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.65 (0.37–1.22)

0≤0.351.4

Missense OE?0.85 (0.73–1.00)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 7 / 10.7Missense obs/exp: 108 / 126.5Syn Z: 0.72

This gene — mechanism propensity

0.86top 5%

GOF

0.87top 5%

LOF

0.1994th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

47 submitted variants in ClinVar

ClinVar

Classification Summary

VUS41

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	41	0	41
Likely Benign	2	2	4
Benign	0	0	0
Total	43	2	45

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

96 pathogenic / likely-pathogenic (of 125) ClinVar copy-number / structural variants overlap CHRFAM7A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →