X-154695978-T-C

Position:

• chrX-154695978-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001081573.3(GAB3):​c.1469A>G​(p.Asn490Ser) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GAB3 NM_001081573.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15503326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAB3	NM_001081573.3	c.1469A>G	p.Asn490Ser	missense_variant	8/10	ENST00000424127.3	NP_001075042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAB3	ENST00000424127.3	c.1469A>G	p.Asn490Ser	missense_variant	8/10	1	NM_001081573.3	ENSP00000399588	A2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 22

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

Aug 04, 2023

The c.1469A>G (p.N490S) alteration is located in exon 8 (coding exon 8) of the GAB3 gene. This alteration results from a A to G substitution at nucleotide position 1469, causing the asparagine (N) at amino acid position 490 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	0.077
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;.
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M;.;.
MutationTaster	Benign	0.62	D;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.038
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.52	P;.;.
Vest4		0.12
MutPred		0.23		Gain of sheet (P = 0.0344);.;.;
MVP		0.55
MPC		0.32
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.096
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-153924253;