X-108732576-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001379150.1(IRS4):c.3766+3C>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,208,331 control chromosomes in the GnomAD database, including 200 homozygotes. There are 1,564 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (109 hom., 748 hem., cov: 23)
  • Exomes 𝑓: 0.0027 (91 hom. 816 hem.)
• Consequence: IRS4 NM_001379150.1 splice_donor_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.100

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-108732576-G-T is Benign according to our data. Variant chrX-108732576-G-T is described in ClinVar as [Benign]. Clinvar id is 777818.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108732576-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRS4	NM_001379150.1	c.3766+3C>A		splice_donor_region_variant, intron_variant		ENST00000372129.4
IRS4	NM_003604.2	c.3769C>A	p.Arg1257=	synonymous_variant	1/1
IRS4	XM_006724713.4	c.3766+3C>A		splice_donor_region_variant, intron_variant
IRS4	XM_011531061.2	c.3766+3C>A		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRS4	ENST00000372129.4	c.3766+3C>A		splice_donor_region_variant, intron_variant			NM_001379150.1	A2
IRS4	ENST00000564206.2	c.3769C>A	p.Arg1257=	synonymous_variant	1/1			P5

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 2840 AN: 111677 Hom.: 109 Cov.: 23 AF XY: 0.0221 AC XY: 749 AN XY: 33873

Gnomad AFR AF: 0.0874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000747

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.0179

GnomAD3 exomes AF: 0.00742 AC: 1362 AN: 183465 Hom.: 46 AF XY: 0.00473 AC XY: 321 AN XY: 67905

Gnomad AFR exome AF: 0.0925

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000610

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00274 AC: 3004 AN: 1096604 Hom.: 91 Cov.: 30 AF XY: 0.00225 AC XY: 816 AN XY: 361980

Gnomad4 AFR exome AF: 0.0936

Gnomad4 AMR exome AF: 0.00500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000333

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000607

Gnomad4 OTH exome AF: 0.00617

GnomAD4 genome AF: 0.0254 AC: 2839 AN: 111727 Hom.: 109 Cov.: 23 AF XY: 0.0220 AC XY: 748 AN XY: 33933

Gnomad4 AFR AF: 0.0872

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000750

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000188

Gnomad4 OTH AF: 0.0177

Alfa AF: 0.00366 Hom.: 20

Bravo AF: 0.0295

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	8.5
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28473027; hg19: chrX-107975806;