4-143438102-A-T

Position:

• chr4-143438102-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002039.4(GAB1):​c.697A>T​(p.Asn233Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GAB1 NM_002039.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.68

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAB1	NM_002039.4	c.697A>T	p.Asn233Tyr	missense_variant	4/10	ENST00000262994.9	NP_002030.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAB1	ENST00000262994.9	c.697A>T	p.Asn233Tyr	missense_variant	4/10	1	NM_002039.4	ENSP00000262994.4
GAB1	ENST00000262995.9	c.697A>T	p.Asn233Tyr	missense_variant	4/11	1		ENSP00000262995.4
GAB1	ENST00000505913.5	c.388A>T	p.Asn130Tyr	missense_variant	4/10	2		ENSP00000424554.1
GAB1	ENST00000512843.1	c.224+4386A>T		intron_variant		4		ENSP00000426297.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Jun 28, 2024

The c.697A>T (p.N233Y) alteration is located in exon 4 (coding exon 4) of the GAB1 gene. This alteration results from a A to T substitution at nucleotide position 697, causing the asparagine (N) at amino acid position 233 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	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	.;D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	N;D;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.88
MutPred		0.24		Gain of methylation at K229 (P = 0.0386);Gain of methylation at K229 (P = 0.0386);.;
MVP		0.67
MPC		1.3
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.37
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-144359255;