rs41307415

Positions:

• chrX-108735113-C-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.1232G>A​(p.Arg411Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,209,567 control chromosomes in the GnomAD database, including 1,524 homozygotes. There are 22,779 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.055 (149 hom., 1681 hem., cov: 22)
  • Exomes 𝑓: 0.059 (1375 hom. 21098 hem.)
• Consequence: IRS4 NM_001379150.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.0540

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 (MetaRNN=0.0016234219).
• BP6: Variant X-108735113-C-T is Benign according to our data. Variant chrX-108735113-C-T is described in ClinVar as [Benign]. Clinvar id is 1284757.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108735113-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS4	NM_001379150.1	c.1232G>A	p.Arg411Gln	missense_variant	1/2	ENST00000372129.4	NP_001366079.1
IRS4	NM_003604.2	c.1232G>A	p.Arg411Gln	missense_variant	1/1		NP_003595.1
IRS4	XM_011531061.2	c.1232G>A	p.Arg411Gln	missense_variant	1/3		XP_011529363.1
IRS4	XM_006724713.4	c.1232G>A	p.Arg411Gln	missense_variant	1/2		XP_006724776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS4	ENST00000372129.4	c.1232G>A	p.Arg411Gln	missense_variant	1/2	6	NM_001379150.1	ENSP00000361202.3
IRS4	ENST00000564206.2	c.1232G>A	p.Arg411Gln	missense_variant	1/1	6		ENSP00000505547.1

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 6137 AN: 111519 Hom.: 148 Cov.: 22 AF XY: 0.0497 AC XY: 1675 AN XY: 33691

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.0161

Gnomad AMR AF: 0.0766

Gnomad ASJ AF: 0.0413

Gnomad EAS AF: 0.00113

Gnomad SAS AF: 0.0565

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.0636

Gnomad NFE AF: 0.0597

Gnomad OTH AF: 0.0669

GnomAD3 exomes AF: 0.0541 AC: 9874 AN: 182612 Hom.: 213 AF XY: 0.0515 AC XY: 3466 AN XY: 67260

Gnomad AFR exome AF: 0.0547

Gnomad AMR exome AF: 0.0839

Gnomad ASJ exome AF: 0.0429

Gnomad EAS exome AF: 0.000577

Gnomad SAS exome AF: 0.0594

Gnomad FIN exome AF: 0.0304

Gnomad NFE exome AF: 0.0576

Gnomad OTH exome AF: 0.0522

GnomAD4 exome AF: 0.0589 AC: 64707 AN: 1097994 Hom.: 1375 Cov.: 34 AF XY: 0.0581 AC XY: 21098 AN XY: 363384

Gnomad4 AFR exome AF: 0.0513

Gnomad4 AMR exome AF: 0.0815

Gnomad4 ASJ exome AF: 0.0406

Gnomad4 EAS exome AF: 0.000232

Gnomad4 SAS exome AF: 0.0583

Gnomad4 FIN exome AF: 0.0325

Gnomad4 NFE exome AF: 0.0623

Gnomad4 OTH exome AF: 0.0556

GnomAD4 genome AF: 0.0551 AC: 6146 AN: 111573 Hom.: 149 Cov.: 22 AF XY: 0.0498 AC XY: 1681 AN XY: 33755

Gnomad4 AFR AF: 0.0507

Gnomad4 AMR AF: 0.0769

Gnomad4 ASJ AF: 0.0413

Gnomad4 EAS AF: 0.00114

Gnomad4 SAS AF: 0.0574

Gnomad4 FIN AF: 0.0360

Gnomad4 NFE AF: 0.0597

Gnomad4 OTH AF: 0.0661

Alfa AF: 0.0565 Hom.: 2596

Bravo AF: 0.0575

TwinsUK AF: 0.0634 AC: 235

ALSPAC AF: 0.0640 AC: 185

ESP6500AA AF: 0.00261 AC: 10

ESP6500EA AF: 0.00446 AC: 30

ExAC AF: 0.0538 AC: 6536

EpiCase AF: 0.0608

EpiControl AF: 0.0591

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.017
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.25	B
Vest4		0.036
MPC		0.62
ClinPred		0.0011	T
GERP RS		2.2
Varity_R		0.093
gMVP		0.28

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: rs41307415; hg19: chrX-107978343; COSMIC: COSV64535293; COSMIC: COSV64535293;