Variant X-154712306-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001081573.3(GAB3):c.992G>A(p.Gly331Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,209,116 control chromosomes in the GnomAD database, including 1 homozygotes. There are 49 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00014 ( 1 hom. 47 hem. )

Consequence

GAB3
NM_001081573.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.291

Variant links:

Genes affected

GAB3 (HGNC:17515): (GRB2 associated binding protein 3) This gene is a member of the GRB2-associated binding protein gene family. These proteins are scaffolding/docking proteins that are involved in several growth factor and cytokine signaling pathways, and they contain a pleckstrin homology domain, and bind SHP2 tyrosine phosphatase and GRB2 adapter protein. The protein encoded by this gene facilitates macrophage differentiation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

GAB3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037780613).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAB3	NM_001081573.3 link	c.992G>A	p.Gly331Asp	missense_variant	4/10	ENST00000424127.3	NP_001075042.1	Q8WWW8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GAB3	ENST00000424127.3 link	c.992G>A	p.Gly331Asp	missense_variant	4/10	1	NM_001081573.3	ENSP00000399588.2	Q8WWW8-2
GAB3	ENST00000369575.7 link	c.989G>A	p.Gly330Asp	missense_variant	4/10	1		ENSP00000358588.3	Q8WWW8-1
GAB3	ENST00000496390.5 link	n.616+901G>A		intron_variant		1
GAB3	ENST00000369568.8 link	c.992G>A	p.Gly331Asp	missense_variant	4/9	2		ENSP00000358581.4	Q8WWW8-3

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111843

Hom.:

Cov.:

AF XY:

0.0000588

AC XY:

AN XY:

33991

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000165

AC:

AN:

181910

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

66434

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000369

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000137

AC:

150

AN:

1097219

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

362609

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000175

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111897

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

34055

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000565

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000598

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2024

The c.992G>A (p.G331D) alteration is located in exon 4 (coding exon 4) of the GAB3 gene. This alteration results from a G to A substitution at nucleotide position 992, causing the glycine (G) at amino acid position 331 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.88

CADD

Benign

8.3

DANN

Benign

0.45

DEOGEN2

Benign

0.18

T;.;.

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.55

T;T;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.038

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

L;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.018

Sift

Benign

0.17

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.19

B;.;.

Vest4

0.062

MutPred

0.14

Loss of glycosylation at S329 (P = 0.0574);.;.;

MVP

0.093

MPC

0.52

ClinPred

0.061

GERP RS

2.7

Varity_R

0.097

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over