chr2-226795333-C-T

Position:

chr2-226795333-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005544.3(IRS1):c.3406G>A(p.Glu1136Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,613,394 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

IRS1
NM_005544.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided U:1B:1

Conservation

PhyloP100: 2.38

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009535074).

BS2

High AC in GnomAd4 at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
IRS1	NM_005544.3 linkuse as main transcript	c.3406G>A	p.Glu1136Lys	missense_variant	1/2	ENST00000305123.6	NP_005535.1
IRS1	XM_047444223.1 linkuse as main transcript	c.3406G>A	p.Glu1136Lys	missense_variant	1/2		XP_047300179.1
IRS1	XM_047444224.1 linkuse as main transcript	c.3406G>A	p.Glu1136Lys	missense_variant	1/2		XP_047300180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRS1	ENST00000305123.6 linkuse as main transcript	c.3406G>A	p.Glu1136Lys	missense_variant	1/2	1	NM_005544.3	ENSP00000304895	P1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000248

AC:

AN:

250132

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

135416

show subpopulations

Gnomad AFR exome

AF:

0.00235

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000475

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000162

AC:

236

AN:

1461062

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

113

AN XY:

726836

show subpopulations

Gnomad4 AFR exome

AF:

0.00281

Gnomad4 AMR exome

AF:

0.000648

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000570

Gnomad4 NFE exome

AF:

0.0000746

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000486

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000150

Hom.:

Bravo

AF:

0.000521

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The IRS1 p.Glu1136Lys variant was identified in the literature somatically in a soft tissue sarcoma tumor from a cohort of 207 sarcoma patients (Barretina_2010_PMID:20601955). The variant was identified in dbSNP (ID: rs200142054) and LOVD 3.0 (classified as likely benign); the variant was not identified in ClinVar. The variant was identified in control databases in 73 of 281490 chromosomes at a frequency of 0.0002593 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 49 of 24882 chromosomes (freq: 0.001969), Latino in 16 of 35412 chromosomes (freq: 0.000452), Other in 2 of 7196 chromosomes (freq: 0.000278), East Asian in 1 of 19918 chromosomes (freq: 0.00005), European (Finnish) in 1 of 24510 chromosomes (freq: 0.000041), South Asian in 1 of 30604 chromosomes (freq: 0.000033) and European (non-Finnish) in 3 of 128634 chromosomes (freq: 0.000023), but was not observed in the Ashkenazi Jewish population. The p.Glu1136 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

IRS1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.033

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.62

M_CAP

Benign

0.013

MetaRNN

Benign

0.0095

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.78

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.1

REVEL

Benign

0.053

Sift

Benign

0.060

Sift4G

Benign

0.36

Polyphen

0.0040

Vest4

0.35

MVP

0.70

MPC

0.30

ClinPred

0.013

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.074

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over