Variant 4-143438248-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002039.4(GAB1):c.843T>A(p.Asp281Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GAB1
NM_002039.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.137

Variant links:

Genes affected

GAB1 (HGNC:4066): (GRB2 associated binding protein 1) The protein encoded by this gene is a member of the IRS1-like multisubstrate docking protein family. It is an important mediator of branching tubulogenesis and plays a central role in cellular growth response, transformation and apoptosis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

GAB1 links:

GAB1 (HGNC:):

GAB1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06600845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAB1	NM_002039.4 linkuse as main transcript	c.843T>A	p.Asp281Glu	missense_variant	4/10	ENST00000262994.9	NP_002030.2	Q13480-1Q9HA84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAB1	ENST00000262994.9 linkuse as main transcript	c.843T>A	p.Asp281Glu	missense_variant	4/10	1	NM_002039.4	ENSP00000262994.4		Q13480-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251220

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

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

Dec 16, 2022

The c.843T>A (p.D281E) alteration is located in exon 4 (coding exon 4) of the GAB1 gene. This alteration results from a T to A substitution at nucleotide position 843, causing the aspartic acid (D) at amino acid position 281 to be replaced by a glutamic acid (E). 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

0.088

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.60

CADD

Benign

4.7

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;T;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.0042

MetaRNN

Benign

0.066

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;N;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.062

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.016

B;B;.

Vest4

0.079

MutPred

0.33

Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);.;

MVP

0.36

MPC

0.37

ClinPred

0.11

GERP RS

-2.0

Varity_R

0.078

gMVP

0.12

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