Genetic Variant NM_005544.3:c.3242G>T (chr2-226795497-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005544.3(IRS1):c.3242G>T(p.Arg1081Leu) 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 1,461,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. R1081C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IRS1
NM_005544.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.421

Publications

0 publications found

Variant links:

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]

IRS1 links:

ENSG00000272622 (HGNC:):

ENSG00000272622 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12363416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRS1	NM_005544.3 link	c.3242G>T	p.Arg1081Leu	missense_variant	Exon 1 of 2	ENST00000305123.6	NP_005535.1	P35568
IRS1	XM_047444223.1 link	c.3242G>T	p.Arg1081Leu	missense_variant	Exon 1 of 2		XP_047300179.1
IRS1	XM_047444224.1 link	c.3242G>T	p.Arg1081Leu	missense_variant	Exon 1 of 2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRS1	ENST00000305123.6 link	c.3242G>T	p.Arg1081Leu	missense_variant	Exon 1 of 2	1	NM_005544.3	ENSP00000304895.4	P35568
ENSG00000272622	ENST00000727652.1 link	n.166+657C>A		intron_variant	Intron 1 of 3
ENSG00000272622	ENST00000727654.1 link	n.71+554C>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.68

M_CAP

Benign

0.053

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

0.42

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.6

REVEL

Benign

0.038

Sift

Benign

0.069

Sift4G

Benign

0.15

Polyphen

0.20

Vest4

0.27

MutPred

0.35

Loss of MoRF binding (P = 0.0283);

MVP

0.67

MPC

0.35

ClinPred

0.20

GERP RS

1.5

Varity_R

0.10

gMVP

0.21

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over