AMMECR1

Chr XXLR

AMMECR nuclear protein 1

Also known as: AMMERC1, MFHIEN

NCBI Gene: 9949 ENSG00000101935 UniProt: Q9Y4X0 OMIM: 300195

The exact function of the AMMECR1 protein is unknown, but deletions involving this gene along with neighboring genes cause AMME complex, characterized by midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis. This X-linked recessive condition is part of a contiguous gene deletion syndrome that affects multiple organ systems including craniofacial development, auditory function, hematologic systems, and kidneys. The gene shows high constraint against loss-of-function variants (pLI 0.82, LOEUF 0.47), suggesting intolerance to protein loss.

OMIM ResearchSummary from RefSeq, OMIM

The exact function of this gene is not known, however, submicroscopic deletion of the X chromosome including this gene, COL4A5, and FACL4 genes, result in a contiguous gene deletion syndrome, the AMME complex (Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLRLOEUF 0.471 OMIM phenotype

Clinical Summary— AMMECR1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.82) — some intolerance to loss-of-function variants.

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ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 56 VUS of 125 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.821

Z-score 2.64

OE 0.10 (0.03–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.08Z-score

OE missense 0.73 (0.61–0.87)

90 obs / 123.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.03–0.47)

0≤0.351.4

Missense OE?0.73 (0.61–0.87)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 1 / 10.0Missense obs/exp: 90 / 123.8Syn Z: 0.27

This gene — mechanism propensity

0.2698th %ile

GOF

0.3788th %ile

LOF

0.84top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 92% of P/LP variants are LoF · LOEUF 0.47

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

125 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic8

VUS56

Likely Benign9

Benign5

Conflicting3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	0	0	0	5
Likely Pathogenic	7	1	0	0	8
VUS	3	49	4	0	56
Likely Benign	0	2	0	7	9
Benign	0	0	3	2	5
Conflicting	—				3
Total	15	52	7	9	86

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

View in ClinVar →

74 pathogenic / likely-pathogenic (of 82) ClinVar copy-number / structural variants overlap AMMECR1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →