rs143523271

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_000208.4(INSR):c.2243C>T(p.Ser748Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,614,056 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 8 hom. )

Consequence

INSR
NM_000208.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:8

Conservation

PhyloP100: 2.80

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 -8 ACMG points.

PP2

Missense variant where missense usually causes diseases, INSR

BP4

Computational evidence support a benign effect (MetaRNN=0.03675735).

BP6

Variant 19-7150521-G-A is Benign according to our data. Variant chr19-7150521-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211190.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=5}. Variant chr19-7150521-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00111 (169/152250) while in subpopulation NFE AF= 0.00209 (142/68052). AF 95% confidence interval is 0.00181. There are 0 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
INSR	NM_000208.4 linkuse as main transcript	c.2243C>T	p.Ser748Leu	missense_variant	11/22	ENST00000302850.10
INSR	XM_011527988.3 linkuse as main transcript	c.2243C>T	p.Ser748Leu	missense_variant	11/22
INSR	NM_001079817.3 linkuse as main transcript	c.2231+2205C>T		intron_variant
INSR	XM_011527989.4 linkuse as main transcript	c.2231+2205C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10 linkuse as main transcript	c.2243C>T	p.Ser748Leu	missense_variant	11/22	1	NM_000208.4	A2	P06213-1
INSR	ENST00000341500.9 linkuse as main transcript	c.2231+2205C>T		intron_variant		1		P3	P06213-2

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

169

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00209

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000796

AC:

200

AN:

251258

Hom.:

AF XY:

0.000751

AC XY:

102

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00157

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00190

AC:

2784

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

1319

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000262

Gnomad4 NFE exome

AF:

0.00244

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.00111

AC:

169

AN:

152250

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00209

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00151

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000700

AC:

EpiCase

AF:

0.00147

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	Reported previously in the heterozygous state with a second INSR variant in a female with type A insulin resistance in childhood who had normal weight and body mass indices (Wei et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28093873, 22939401) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 18, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 12, 2015

- -

Rabson-Mendenhall syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Leprechaunism syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

INSR-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 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). -

Monogenic diabetes

Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Mar 24, 2017

ACMG Criteria:BS2 (6 controls in T2DM), PP3 (2 predictors), BP4 (6 predictors) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

Cadd

Benign

Dann

Benign

0.90

DEOGEN2

Benign

0.39

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.53

M_CAP

Benign

0.049

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.79

REVEL

Benign

0.13

Sift

Benign

0.16

Sift4G

Benign

0.36

Polyphen

0.0

Vest4

0.34

MVP

0.86

MPC

0.69

ClinPred

0.023

GERP RS

4.2

Varity_R

0.076

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.41

Position offset: 11

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