rs4675095

Positions:

• chr2-226787251-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005544.3(IRS1):​c.*21+7738T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0565 in 152,222 control chromosomes in the GnomAD database, including 397 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.057 (397 hom., cov: 32)
• Consequence: IRS1 NM_005544.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.443

Genes affected

IRS1 (HGNC:6125): (insulin receptor substrate 1) This gene encodes a protein which is phosphorylated by insulin receptor tyrosine kinase. Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRS1	NM_005544.3	c.*21+7738T>A		intron_variant		ENST00000305123.6	NP_005535.1
IRS1	XM_047444224.1	c.*22-940T>A		intron_variant			XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6	c.*21+7738T>A		intron_variant		1	NM_005544.3	ENSP00000304895	P1

Frequencies

GnomAD3 genomes AF: 0.0565 AC: 8587 AN: 152104 Hom.: 394 Cov.: 32

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0572

Gnomad OTH AF: 0.0727

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

GnomAD4 genome AF: 0.0565 AC: 8607 AN: 152222 Hom.: 397 Cov.: 32 AF XY: 0.0570 AC XY: 4240 AN XY: 74430

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.150

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.0216

Gnomad4 NFE AF: 0.0573

Gnomad4 OTH AF: 0.0810

Alfa AF: 0.0517 Hom.: 37

Bravo AF: 0.0644

Asia WGS AF: 0.139 AC: 484 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.78
DANN	Benign	0.56

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: rs4675095; hg19: chr2-227651967;