X-154712546-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001081573.3(GAB3):​c.752C>T​(p.Ser251Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,184,514 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 0.000014 ( 0 hom. 6 hem. )

Consequence

GAB3
NM_001081573.3 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0470
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.046773016).
BS2
High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GAB3NM_001081573.3 linkuse as main transcriptc.752C>T p.Ser251Leu missense_variant 4/10 ENST00000424127.3 NP_001075042.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GAB3ENST00000424127.3 linkuse as main transcriptc.752C>T p.Ser251Leu missense_variant 4/101 NM_001081573.3 ENSP00000399588 A2Q8WWW8-2
GAB3ENST00000369575.7 linkuse as main transcriptc.749C>T p.Ser250Leu missense_variant 4/101 ENSP00000358588 P4Q8WWW8-1
GAB3ENST00000496390.5 linkuse as main transcriptn.616+661C>T intron_variant, non_coding_transcript_variant 1
GAB3ENST00000369568.8 linkuse as main transcriptc.752C>T p.Ser251Leu missense_variant 4/92 ENSP00000358581 A2Q8WWW8-3

Frequencies

GnomAD3 genomes
AF:
0.0000179
AC:
2
AN:
111725
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33939
show subpopulations
Gnomad AFR
AF:
0.0000326
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000384
AC:
6
AN:
156437
Hom.:
0
AF XY:
0.0000401
AC XY:
2
AN XY:
49925
show subpopulations
Gnomad AFR exome
AF:
0.000156
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000151
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000282
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000140
AC:
15
AN:
1072789
Hom.:
0
Cov.:
30
AF XY:
0.0000173
AC XY:
6
AN XY:
347043
show subpopulations
Gnomad4 AFR exome
AF:
0.0000775
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000666
Gnomad4 SAS exome
AF:
0.0000203
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000121
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000179
AC:
2
AN:
111725
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33939
show subpopulations
Gnomad4 AFR
AF:
0.0000326
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ESP6500AA
AF:
0.000261
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000497
AC:
6

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.752C>T (p.S251L) alteration is located in exon 4 (coding exon 4) of the GAB3 gene. This alteration results from a C to T substitution at nucleotide position 752, causing the serine (S) at amino acid position 251 to be replaced by a leucine (L). 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
0.066
BayesDel_addAF
Benign
-0.69
T
BayesDel_noAF
Benign
-0.97
CADD
Benign
0.0090
DANN
Benign
0.17
DEOGEN2
Benign
0.12
T;.;.
FATHMM_MKL
Benign
0.043
N
LIST_S2
Benign
0.66
T;T;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.047
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.34
N;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-1.4
N;N;N
REVEL
Benign
0.021
Sift
Benign
0.39
T;T;T
Sift4G
Benign
0.57
T;T;T
Polyphen
0.0
B;.;.
Vest4
0.021
MVP
0.043
MPC
0.28
ClinPred
0.0042
T
GERP RS
-3.3
Varity_R
0.039
gMVP
0.10

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138147469; hg19: chrX-153940821; API