ZMYM2

Chr 13AD

zinc finger MYM-type containing 2

Also known as: FIM, MYM, NECRC, RAMP, SCLL, ZNF198

NCBI Gene: 7750 ENSG00000121741 UniProt: Q9UBW7 OMIM: 602221

The encoded zinc finger protein functions as a transcriptional repressor and is part of a histone deacetylase complex involved in chromatin regulation. Mutations cause neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (LOEUF 0.332), reflecting its critical role in normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a zinc finger protein that may act as a transcription factor. The encoded protein may be part of a BHC histone deacetylase complex. Translocation of this gene with the fibroblast growth factor receptor-1 gene (FGFR1) results in a fusion gene, which may be a cause of stem cell leukemia lymphoma syndrome (SCLL). Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.331 OMIM phenotype

Clinical Summary— ZMYM2

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Gene-Disease Validity (ClinGen)

syndromic complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.67) — some intolerance to loss-of-function variants.

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ClinVar Variants

106 unique Pathogenic / Likely Pathogenic· 255 VUS of 430 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.666

Z-score 6.06

OE 0.22 (0.14–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.01Z-score

OE missense 0.67 (0.62–0.73)

451 obs / 670.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.22 (0.14–0.33)

0≤0.351.4

Missense OE?0.67 (0.62–0.73)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 15 / 69.5Missense obs/exp: 451 / 670.7Syn Z: 1.17

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongZMYM2-related developmental disorderLOFAD

This gene — mechanism propensity

0.3296th %ile

GOF

0.3094th %ile

LOF

0.67top 25%

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

LOFprediction above median · 1 literature citation · 97% of P/LP variants are LoF · LOEUF 0.33

Literature Evidence

LOFThrough collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families.1

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

References

1.PMID 32891193 ↗

ClinVar Variant Classifications

430 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45

Likely Pathogenic61

VUS255

Likely Benign25

Benign8

Conflicting2

Pathogenic

Likely Pathogenic

255

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	45	0	0	0	45
Likely Pathogenic	58	0	3	0	61
VUS	14	230	10	1	255
Likely Benign	0	9	2	14	25
Benign	0	1	2	5	8
Conflicting	—				2
Total	117	240	17	20	396

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

View in ClinVar →

44 pathogenic / likely-pathogenic (of 74) ClinVar copy-number / structural variants overlap ZMYM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →