chrX-154712550-A-T

Position:

• chrX-154712550-A-T

Variant summary

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

The NM_001081573.3(GAB3):​c.748T>A​(p.Ser250Thr) 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. 13/20 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: 0.804

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=0.09056893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAB3	NM_001081573.3	c.748T>A	p.Ser250Thr	missense_variant	4/10	ENST00000424127.3	NP_001075042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAB3	ENST00000424127.3	c.748T>A	p.Ser250Thr	missense_variant	4/10	1	NM_001081573.3	ENSP00000399588.2
GAB3	ENST00000369575.7	c.745T>A	p.Ser249Thr	missense_variant	4/10	1		ENSP00000358588.3
GAB3	ENST00000496390.5	n.616+657T>A		intron_variant		1
GAB3	ENST00000369568.8	c.748T>A	p.Ser250Thr	missense_variant	4/9	2		ENSP00000358581.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

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

Nov 25, 2024

The c.748T>A (p.S250T) alteration is located in exon 4 (coding exon 4) of the GAB3 gene. This alteration results from a T to A substitution at nucleotide position 748, causing the serine (S) at amino acid position 250 to be replaced by a threonine (T). 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	0.080
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.4
DANN	Benign	0.34
DEOGEN2	Benign	0.10	T;.;.
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.69	N;N;N
REVEL	Benign	0.041
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.013	B;.;.
Vest4		0.076
MutPred		0.24		Gain of relative solvent accessibility (P = 0.0082);.;.;
MVP		0.53
MPC		0.33
ClinPred		0.12	T
GERP RS		0.31
Varity_R		0.092
gMVP		0.18

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-153940825;