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4-143438452-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_002039.4(GAB1):c.1047T>C(p.His349=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000282 in 1,613,900 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00044 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

GAB1
NM_002039.4 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.602
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 4-143438452-T-C is Benign according to our data. Variant chr4-143438452-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3044038.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.602 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GAB1NM_002039.4 linkuse as main transcriptc.1047T>C p.His349= synonymous_variant 4/10 ENST00000262994.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GAB1ENST00000262994.9 linkuse as main transcriptc.1047T>C p.His349= synonymous_variant 4/101 NM_002039.4 A1Q13480-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000441
AC:
67
AN:
151954
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000967
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00380
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000387
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00108
AC:
272
AN:
251020
Hom.:
0
AF XY:
0.000818
AC XY:
111
AN XY:
135660
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00712
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000218
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000441
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.000265
AC:
388
AN:
1461828
Hom.:
0
Cov.:
32
AF XY:
0.000235
AC XY:
171
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.00754
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.000414
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000441
AC:
67
AN:
152072
Hom.:
1
Cov.:
32
AF XY:
0.000511
AC XY:
38
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000964
Gnomad4 AMR
AF:
0.00380
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000388
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000164
Hom.:
0
Bravo
AF:
0.000960
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

GAB1-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMay 28, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.72
Cadd
Benign
5.7
Dann
Benign
0.39

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: rs201285291; hg19: chr4-144359605; API