4-143438159-G-T

Position:

• chr4-143438159-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002039.4(GAB1):​c.754G>T​(p.Ala252Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: GAB1 NM_002039.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.515

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]

ACMG classification

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=0.023925245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAB1	NM_002039.4	c.754G>T	p.Ala252Ser	missense_variant	4/10	ENST00000262994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAB1	ENST00000262994.9	c.754G>T	p.Ala252Ser	missense_variant	4/10	1	NM_002039.4	A1
GAB1	ENST00000262995.9	c.754G>T	p.Ala252Ser	missense_variant	4/11	1		P3
GAB1	ENST00000505913.5	c.445G>T	p.Ala149Ser	missense_variant	4/10	2
GAB1	ENST00000512843.1	c.226+4443G>T		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2021

The c.754G>T (p.A252S) alteration is located in exon 4 (coding exon 4) of the GAB1 gene. This alteration results from a G to T substitution at nucleotide position 754, causing the alanine (A) at amino acid position 252 to be replaced by a serine (S). 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	0.069
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.4
DANN	Benign	0.77
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.024	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.050	N;N;N
REVEL	Benign	0.065
Sift	Benign	0.79	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.20
MutPred		0.14		Gain of phosphorylation at A252 (P = 0.0075);Gain of phosphorylation at A252 (P = 0.0075);.;
MVP		0.36
MPC		0.35
ClinPred		0.046	T
GERP RS		1.4
Varity_R		0.030
gMVP		0.13

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

Other links and lift over

dbSNP: rs1406763279; hg19: chr4-144359312;