X-154695973-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001081573.3(GAB3):​c.1474G>A​(p.Ala492Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000369 in 1,084,318 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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)
Exomes 𝑓: 0.0000037 ( 0 hom. 1 hem. )

Consequence

GAB3
NM_001081573.3 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.54
Variant links:
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]

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ACMG classification

Classification made for transcript

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=0.11471009).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GAB3NM_001081573.3 linkuse as main transcriptc.1474G>A p.Ala492Thr missense_variant 8/10 ENST00000424127.3 NP_001075042.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GAB3ENST00000424127.3 linkuse as main transcriptc.1474G>A p.Ala492Thr missense_variant 8/101 NM_001081573.3 ENSP00000399588 A2Q8WWW8-2

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
AF:
0.00000369
AC:
4
AN:
1084318
Hom.:
0
Cov.:
25
AF XY:
0.00000285
AC XY:
1
AN XY:
350700
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000482
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22

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 submitterclinical testingAmbry GeneticsAug 04, 2023The c.1474G>A (p.A492T) alteration is located in exon 8 (coding exon 8) of the GAB3 gene. This alteration results from a G to A substitution at nucleotide position 1474, causing the alanine (A) at amino acid position 492 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
0.082
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.80
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Benign
0.12
T;.;.
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.80
T;T;T
M_CAP
Benign
0.0079
T
MetaRNN
Benign
0.11
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.8
L;.;.
MutationTaster
Benign
0.56
D;D;D
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.14
N;N;N
REVEL
Benign
0.099
Sift
Benign
0.50
T;T;T
Sift4G
Benign
0.59
T;T;T
Polyphen
0.89
P;.;.
Vest4
0.060
MutPred
0.23
Gain of phosphorylation at A491 (P = 0.0543);.;.;
MVP
0.36
MPC
0.34
ClinPred
0.64
D
GERP RS
4.6
Varity_R
0.069
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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-153924248; API