rs1553950635

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV000883155: Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/29408807).".

• 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
• Publications: 0 publications found

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]

GAB1 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 26

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000883155: Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/29408807).
• 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 VariationId is 545492.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002039.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAB1	NM_002039.4	MANE Select	c.347G>A	p.Gly116Glu	missense	Exon 2 of 10	NP_002030.2
	GAB1	NM_207123.3		c.347G>A	p.Gly116Glu	missense	Exon 2 of 11	NP_997006.1	Q13480-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAB1	ENST00000262994.9	TSL:1 MANE Select	c.347G>A	p.Gly116Glu	missense	Exon 2 of 10	ENSP00000262994.4	Q13480-1
	GAB1	ENST00000262995.9	TSL:1	c.347G>A	p.Gly116Glu	missense	Exon 2 of 11	ENSP00000262995.4	Q13480-2
	GAB1	ENST00000882513.1		c.347G>A	p.Gly116Glu	missense	Exon 2 of 12	ENSP00000552572.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33166

American (AMR) AF: 0.00 AC: 0 AN: 43854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106066

Other (OTH) AF: 0.00 AC: 0 AN: 60046

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal recessive nonsyndromic hearing loss 26 (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.37		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
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553950635; hg19: chr4-144336904;