rs3731594

Variant names:

• chr2-226795330-C-A
• rs3731594
• NM_005544.3:c.3409G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-226795330-C-A
• chr2-226795330-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005544.3(IRS1):​c.3409G>T​(p.Asp1137Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,178 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1137N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IRS1 NM_005544.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3	c.3409G>T	p.Asp1137Tyr	missense_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1	c.3409G>T	p.Asp1137Tyr	missense_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1	c.3409G>T	p.Asp1137Tyr	missense_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.3409G>T	p.Asp1137Tyr	missense_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4
ENSG00000272622	ENST00000727652.1	n.166+490C>A		intron_variant	Intron 1 of 3
ENSG00000272622	ENST00000727654.1	n.71+387C>A		intron_variant	Intron 1 of 3
IRS1	ENST00000498335.1	n.-84G>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461178 Hom.: 0 Cov.: 42 AF XY: 0.00 AC XY: 0 AN XY: 726902

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.097
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.021	D
Polyphen		0.92	P
Vest4		0.34
MutPred		0.11		Gain of phosphorylation at D1137 (P = 0.0292);
MVP		0.85
MPC		0.72
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.35
gMVP		0.32
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs3731594; hg19: chr2-227660046;