TRA2B

Chr 3AD

transformer 2 beta homolog

Also known as: Htra2-beta, PPP1R156, RAMELN, SFRS10, SRFS10, TRA2-BETA, TRAN2B

NCBI Gene: 6434 ENSG00000136527 UniProt: P62995 OMIM: 602719

The protein functions as a sequence-specific serine/arginine splicing factor that controls pre-mRNA splicing by either activating or suppressing exon inclusion, including regulation of the survival motor neuron SMN2 gene. Mutations cause autosomal dominant developmental delay with or without dysmorphic facies and autism. This gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a nuclear protein which functions as sequence-specific serine/arginine splicing factor which plays a role in mRNA processing, splicing patterns, and gene expression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.251 OMIM phenotype

Clinical Summary— TRA2B

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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)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 22 VUS of 45 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.25LOEUF

pLI 0.993

Z-score 3.86

OE 0.05 (0.02–0.25)

Highly constrained

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

Missense Constraint?

3.50Z-score

OE missense 0.30 (0.24–0.37)

60 obs / 198.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.25)

0≤0.351.4

Missense OE?0.30 (0.24–0.37)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 1 / 19.3Missense obs/exp: 60 / 198.7Syn Z: 0.04

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateTRA2B-related neurodevelopmental syndromeOTHERAD

This gene — mechanism propensity

0.3196th %ile

GOF

0.3292th %ile

LOF

0.88top 5%

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

LOFprediction above median · 50% of P/LP variants are LoF · LOEUF 0.25

DN1 literature citation

Literature Evidence

DNCONCLUSION: Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2Î² pro1

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 36549593 ↗

ClinVar Variant Classifications

45 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

VUS22

Pathogenic

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Total
Pathogenic	3	2	1	6
Likely Pathogenic	0	0	0	0
VUS	5	16	1	22
Likely Benign	0	0	0	0
Benign	0	0	0	0
Total	8	18	2	28

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

View in ClinVar →

41 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap TRA2B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →