Variant X-154712546-G-A 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.752C>T(p.Ser251Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,184,514 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 6 hem. )

Consequence

GAB3
NM_001081573.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0470

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:

GAB3 (HGNC:):

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=0.046773016).

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAB3	NM_001081573.3 linkuse as main transcript	c.752C>T	p.Ser251Leu	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 linkuse as main transcript	c.752C>T	p.Ser251Leu	missense_variant	4/10	1	NM_001081573.3	ENSP00000399588.2	Q8WWW8-2
GAB3	ENST00000369575.7 linkuse as main transcript	c.749C>T	p.Ser250Leu	missense_variant	4/10	1		ENSP00000358588.3	Q8WWW8-1
GAB3	ENST00000496390.5 linkuse as main transcript	n.616+661C>T		intron_variant		1
GAB3	ENST00000369568.8 linkuse as main transcript	c.752C>T	p.Ser251Leu	missense_variant	4/9	2		ENSP00000358581.4	Q8WWW8-3

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111725

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33939

show subpopulations

Gnomad AFR

AF:

0.0000326

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000384

AC:

AN:

156437

Hom.:

AF XY:

0.0000401

AC XY:

AN XY:

49925

show subpopulations

Gnomad AFR exome

AF:

0.000156

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000151

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000282

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000140

AC:

AN:

1072789

Hom.:

Cov.:

AF XY:

0.0000173

AC XY:

AN XY:

347043

show subpopulations

Gnomad4 AFR exome

AF:

0.0000775

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000666

Gnomad4 SAS exome

AF:

0.0000203

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000121

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111725

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33939

show subpopulations

Gnomad4 AFR

AF:

0.0000326

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000497

AC:

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 04, 2023

The c.752C>T (p.S251L) alteration is located in exon 4 (coding exon 4) of the GAB3 gene. This alteration results from a C to T substitution at nucleotide position 752, causing the serine (S) at amino acid position 251 to be replaced by a leucine (L). 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

0.066

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.0090

DANN

Benign

0.17

DEOGEN2

Benign

0.12

T;.;.

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.66

T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.047

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

N;.;.

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.021

Sift

Benign

0.39

T;T;T

Sift4G

Benign

0.57

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.021

MVP

0.043

MPC

0.28

ClinPred

0.0042

GERP RS

-3.3

Varity_R

0.039

gMVP

0.10

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