X-108733179-TACAGC-T

Position:

• chrX-108733179-TACAGC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001379150.1(IRS4):​c.3161_3165del​(p.Cys1054TyrfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: IRS4 NM_001379150.1 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.53

Genes affected

IRS4 (HGNC:6128): (insulin receptor substrate 4) IRS4 encodes the insulin receptor substrate 4, a cytoplasmic protein that contains many potential tyrosine and serine/threonine phosphorylation sites. Tyrosine-phosphorylated IRS4 protein has been shown to associate with cytoplasmic signalling molecules that contain SH2 domains. The IRS4 protein is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation.. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.162 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108733179-TACAGC-T is Pathogenic according to our data. Variant chrX-108733179-TACAGC-T is described in ClinVar as [Pathogenic]. Clinvar id is 691494.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS4	NM_001379150.1	c.3161_3165del	p.Cys1054TyrfsTer12	frameshift_variant	1/2	ENST00000372129.4
IRS4	NM_003604.2	c.3161_3165del	p.Cys1054TyrfsTer12	frameshift_variant	1/1
IRS4	XM_006724713.4	c.3161_3165del	p.Cys1054TyrfsTer12	frameshift_variant	1/2
IRS4	XM_011531061.2	c.3161_3165del	p.Cys1054TyrfsTer12	frameshift_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS4	ENST00000372129.4	c.3161_3165del	p.Cys1054TyrfsTer12	frameshift_variant	1/2		NM_001379150.1	A2
IRS4	ENST00000564206.2	c.3161_3165del	p.Cys1054TyrfsTer12	frameshift_variant	1/1			P5

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypothyroidism, congenital, nongoitrous, 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1603336347; hg19: chrX-107976409;