rs13306465

Variant names:

• chr2-226799185-C-T
• rs13306465
• NM_005544.3:c.-447G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005544.3(IRS1):​c.-447G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,105,064 control chromosomes in the GnomAD database, including 4,613 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 0.13 (2609 hom., cov: 32)
  • Exomes 𝑓: 0.038 (2004 hom.)
• Consequence: IRS1 NM_005544.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.648
• Publications: 6 publications found

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]

ENSG00000272622 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3	c.-447G>A		5_prime_UTR_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1	c.-447G>A		5_prime_UTR_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1	c.-447G>A		5_prime_UTR_variant	Exon 1 of 2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6	c.-447G>A		5_prime_UTR_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19549 AN: 151852 Hom.: 2603 Cov.: 32

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0910

Gnomad ASJ AF: 0.0665

Gnomad EAS AF: 0.0938

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0368

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.0377 AC: 35928 AN: 953094 Hom.: 2004 Cov.: 34 AF XY: 0.0390 AC XY: 17515 AN XY: 449478

African (AFR) AF: 0.368 AC: 6141 AN: 16668

American (AMR) AF: 0.0679 AC: 367 AN: 5402

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 397 AN: 7222

East Asian (EAS) AF: 0.0728 AC: 430 AN: 5910

South Asian (SAS) AF: 0.128 AC: 4903 AN: 38296

European-Finnish (FIN) AF: 0.0372 AC: 733 AN: 19688

Middle Eastern (MID) AF: 0.0823 AC: 164 AN: 1992

European-Non Finnish (NFE) AF: 0.0254 AC: 20924 AN: 825314

Other (OTH) AF: 0.0573 AC: 1869 AN: 32602

GnomAD4 genome AF: 0.129 AC: 19579 AN: 151970 Hom.: 2609 Cov.: 32 AF XY: 0.128 AC XY: 9542 AN XY: 74284

African (AFR) AF: 0.339 AC: 14055 AN: 41426

American (AMR) AF: 0.0914 AC: 1398 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0665 AC: 231 AN: 3472

East Asian (EAS) AF: 0.0944 AC: 483 AN: 5116

South Asian (SAS) AF: 0.141 AC: 680 AN: 4818

European-Finnish (FIN) AF: 0.0368 AC: 390 AN: 10602

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0306 AC: 2081 AN: 67920

Other (OTH) AF: 0.109 AC: 230 AN: 2108

Alfa AF: 0.109 Hom.: 1431

Bravo AF: 0.141

Asia WGS AF: 0.124 AC: 432 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.96
PhyloP100		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs13306465; hg19: chr2-227663901;