Variant X-154697136-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001081573.3(GAB3):c.1423C>G(p.Pro475Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000124 in 1,202,398 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 55 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.00013 ( 0 hom. 55 hem. )

Consequence

GAB3
NM_001081573.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.58

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 Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 55 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAB3	NM_001081573.3 link	c.1423C>G	p.Pro475Ala	missense_variant	7/10	ENST00000424127.3	NP_001075042.1	Q8WWW8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GAB3	ENST00000424127.3 link	c.1423C>G	p.Pro475Ala	missense_variant	7/10	1	NM_001081573.3	ENSP00000399588.2	Q8WWW8-2
GAB3	ENST00000369575.7 link	c.1420C>G	p.Pro474Ala	missense_variant	7/10	1		ENSP00000358588.3	Q8WWW8-1
GAB3	ENST00000496390.5 link	n.970C>G		non_coding_transcript_exon_variant	6/9	1
GAB3	ENST00000369568.8 link	c.1423C>G	p.Pro475Ala	missense_variant	7/9	2		ENSP00000358581.4	Q8WWW8-3

Frequencies

GnomAD3 genomes

AF:

0.0000445

AC:

AN:

112410

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34556

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:

0.0000563

Gnomad OTH

AF:

0.00133

GnomAD3 exomes

AF:

0.0000896

AC:

AN:

178500

Hom.:

AF XY:

0.000127

AC XY:

AN XY:

63214

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:

0.000201

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000132

AC:

144

AN:

1089988

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

AN XY:

356002

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:

0.000168

Gnomad4 OTH exome

AF:

0.0000873

GnomAD4 genome

AF:

0.0000445

AC:

AN:

112410

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34556

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:

0.0000563

Gnomad4 OTH

AF:

0.00133

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000906

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

Oct 12, 2024

The c.1423C>G (p.P475A) alteration is located in exon 7 (coding exon 7) of the GAB3 gene. This alteration results from a C to G substitution at nucleotide position 1423, causing the proline (P) at amino acid position 475 to be replaced by an alanine (A). 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

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

D;.;.

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.83

T;T;T

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.2

M;.;.

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Benign

0.28

Sift

Benign

0.033

D;D;D

Sift4G

Uncertain

0.048

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.61

MutPred

0.40

Loss of sheet (P = 0.0228);.;.;

MVP

0.53

MPC

1.0

ClinPred

0.46

GERP RS

5.1

Varity_R

0.29

gMVP

0.35

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