Variant X-154716149-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.253G>A(p.Val85Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,211,120 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., 13 hem., cov: 24)

Exomes 𝑓: 0.000059 ( 0 hom. 19 hem. )

Consequence

GAB3
NM_001081573.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.38

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.067058176).

BS2

High Hemizygotes in GnomAd4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAB3	NM_001081573.3 linkuse as main transcript	c.253G>A	p.Val85Met	missense_variant	2/10	ENST00000424127.3	NP_001075042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAB3	ENST00000424127.3 linkuse as main transcript	c.253G>A	p.Val85Met	missense_variant	2/10	1	NM_001081573.3	ENSP00000399588	A2	Q8WWW8-2
GAB3	ENST00000369575.7 linkuse as main transcript	c.253G>A	p.Val85Met	missense_variant	2/10	1		ENSP00000358588	P4	Q8WWW8-1
GAB3	ENST00000496390.5 linkuse as main transcript	n.273G>A		non_coding_transcript_exon_variant	2/9	1
GAB3	ENST00000369568.8 linkuse as main transcript	c.253G>A	p.Val85Met	missense_variant	2/9	2		ENSP00000358581	A2	Q8WWW8-3

Frequencies

GnomAD3 genomes

AF:

0.000478

AC:

AN:

112947

Hom.:

Cov.:

AF XY:

0.000342

AC XY:

AN XY:

35093

show subpopulations

Gnomad AFR

AF:

0.00158

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000279

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:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000136

AC:

AN:

183487

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

67919

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000592

AC:

AN:

1098120

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

363476

show subpopulations

Gnomad4 AFR exome

AF:

0.00121

Gnomad4 AMR exome

AF:

0.000199

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000487

AC:

AN:

113000

Hom.:

Cov.:

AF XY:

0.000370

AC XY:

AN XY:

35156

show subpopulations

Gnomad4 AFR

AF:

0.00160

Gnomad4 AMR

AF:

0.000278

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000240

Hom.:

Bravo

AF:

0.000586

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Feb 17, 2022

The c.253G>A (p.V85M) alteration is located in exon 2 (coding exon 2) of the GAB3 gene. This alteration results from a G to A substitution at nucleotide position 253, causing the valine (V) at amino acid position 85 to be replaced by a methionine (M). 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

Uncertain

0.43

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

T;.;.

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.067

T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.5

L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.8

N;N;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.18

MVP

0.79

MPC

1.0

ClinPred

0.099

GERP RS

5.0

Varity_R

0.57

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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