rs1553950635

Variant names:

• chr4-143415751-G-A
• rs1553950635
• NM_002039.4:c.347G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_002039.4(GAB1):​c.347G>A​(p.Gly116Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAB1 NM_002039.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.90

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763
• PP5: Variant 4-143415751-G-A is Pathogenic according to our data. Variant chr4-143415751-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 545492.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAB1	NM_002039.4	c.347G>A	p.Gly116Glu	missense_variant	Exon 2 of 10	ENST00000262994.9	NP_002030.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAB1	ENST00000262994.9	c.347G>A	p.Gly116Glu	missense_variant	Exon 2 of 10	1	NM_002039.4	ENSP00000262994.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452642 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 721200

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: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 26 Pathogenic:2

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Pathogenic, for Deafness, autosomal recessive, 26. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1-Moderate => PP1 upgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29408807). PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (https://prosite.expasy.org/PDOC50003) (https://www.uniprot.org/uniprot/Q13480) (https://www.ncbi.nlm.nih.gov/pubmed/29408807). PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/29408807). -

Aug 06, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D;D;.;D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.7	M;M;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.0	D;D;D;D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.89
MutPred		0.37		Gain of disorder (P = 0.0767);Gain of disorder (P = 0.0767);Gain of disorder (P = 0.0767);.;.;.;
MVP		0.73
MPC		1.4
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.86
gMVP		0.57

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

Other links and lift over

dbSNP: rs1553950635; hg19: chr4-144336904;