Variant chrX-154699414-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001081573.3(GAB3):c.1225C>T(p.His409Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 1,208,858 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 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., 1 hem., cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )

Consequence

GAB3
NM_001081573.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.050896257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAB3	NM_001081573.3 link	c.1225C>T	p.His409Tyr	missense_variant	6/10	ENST00000424127.3	NP_001075042.1	Q8WWW8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GAB3	ENST00000424127.3 link	c.1225C>T	p.His409Tyr	missense_variant	6/10	1	NM_001081573.3	ENSP00000399588.2	Q8WWW8-2
GAB3	ENST00000369575.7 link	c.1222C>T	p.His408Tyr	missense_variant	6/10	1		ENSP00000358588.3	Q8WWW8-1
GAB3	ENST00000496390.5 link	n.772C>T		non_coding_transcript_exon_variant	5/9	1
GAB3	ENST00000369568.8 link	c.1225C>T	p.His409Tyr	missense_variant	6/9	2		ENSP00000358581.4	Q8WWW8-3

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111681

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33833

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000951

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:

0.00

Gnomad OTH

AF:

0.000673

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183100

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67650

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1097177

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362541

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:

0.00

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111681

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33833

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000951

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000673

Bravo

AF:

0.0000680

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 19, 2024

The c.1225C>T (p.H409Y) alteration is located in exon 6 (coding exon 6) of the GAB3 gene. This alteration results from a C to T substitution at nucleotide position 1225, causing the histidine (H) at amino acid position 409 to be replaced by a tyrosine (Y). 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

0.070

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.85

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

T;.;.

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.63

T;T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.051

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.7

L;.;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.063

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.10

MutPred

0.18

Gain of phosphorylation at H408 (P = 0.0181);.;.;

MVP

0.14

MPC

0.36

ClinPred

0.062

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.19

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