NM_000208.4:c.2971C>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1PP2BP4_StrongBP6_Very_StrongBS1

The NM_000208.4(INSR):c.2971C>A(p.Leu991Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,565,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

INSR
NM_000208.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.60

Variant links:

Genes affected

INSR (HGNC:6091): (insulin receptor) This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

INSR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PM1

In a mutagenesis_site Reduces interaction with IRS1 but has no effect on interaction with SHC1. (size 0) in uniprot entity INSR_HUMAN

PP2

Missense variant in the INSR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8314 (above the threshold of 3.09). Trascript score misZ: 5.4593 (above the threshold of 3.09). GenCC associations: The gene is linked to insulin-resistance syndrome type A, hyperinsulinism due to INSR deficiency, Rabson-Mendenhall syndrome, Donohue syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.015149355).

BP6

Variant 19-7126626-G-T is Benign according to our data. Variant chr19-7126626-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 211196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00275 (419/152284) while in subpopulation AFR AF= 0.00953 (396/41552). AF 95% confidence interval is 0.00876. There are 0 homozygotes in gnomad4. There are 201 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.2971C>A	p.Leu991Ile	missense_variant	Exon 16 of 22	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.2935C>A	p.Leu979Ile	missense_variant	Exon 15 of 21		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.2968C>A	p.Leu990Ile	missense_variant	Exon 16 of 22		XP_011526290.2
INSR	XM_011527989.4 link	c.2932C>A	p.Leu978Ile	missense_variant	Exon 15 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10 link	c.2971C>A	p.Leu991Ile	missense_variant	Exon 16 of 22	1	NM_000208.4	ENSP00000303830.4		P06213-1
INSR	ENST00000341500.9 link	c.2935C>A	p.Leu979Ile	missense_variant	Exon 15 of 21	1		ENSP00000342838.4		P06213-2

Frequencies

GnomAD3 genomes

AF:

0.00275

AC:

419

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00956

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000485

AC:

AN:

177380

Hom.:

AF XY:

0.000435

AC XY:

AN XY:

94254

show subpopulations

Gnomad AFR exome

AF:

0.00730

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000832

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000277

AC:

391

AN:

1413226

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

161

AN XY:

698178

show subpopulations

Gnomad4 AFR exome

AF:

0.00956

Gnomad4 AMR exome

AF:

0.000582

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000249

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.000735

GnomAD4 genome

AF:

0.00275

AC:

419

AN:

152284

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

201

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00953

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000604

Hom.:

Bravo

AF:

0.00319

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00659

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000454

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 31, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monogenic diabetes

Benign:1

Mar 16, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: PP3 (4 predictors), BP4 (6 predictors), BS2 (12 controls and 12 cases from T2DM), BS1 (1% MAF in 1000g and ExAC African, but disease frequency of AD form is 1 in 100,000) NOTE: called VUS by Chicago=benign -

not provided

Benign:1

Apr 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperinsulinism due to INSR deficiency

Benign:1

Sep 01, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

INSR-related disorder

Benign:1

Mar 18, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

0.17

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

9.1

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

.;D

Eigen

Benign

-0.096

Eigen_PC

Benign

-0.099

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.23

Sift

Benign

0.046

D;D

Sift4G

Benign

0.080

T;T

Polyphen

0.58

P;B

Vest4

0.21

MVP

0.81

MPC

1.1

ClinPred

0.027

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.45

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