rs76077021

Positions:

chr19-7141694-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP2BS1_Supporting

The NM_000208.4(INSR):c.2665C>T(p.Arg889Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000296 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

INSR
NM_000208.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 1.64

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain Fibronectin type-III 3 (size 94) in uniprot entity INSR_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_000208.4

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), INSR. . Gene score misZ 3.8314 (greater than the threshold 3.09). Trascript score misZ 5.4593 (greater than threshold 3.09). GenCC has associacion of gene with insulin-resistance syndrome type A, hyperinsulinism due to INSR deficiency, Rabson-Mendenhall syndrome, Donohue syndrome.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000197 (30/152210) while in subpopulation NFE AF= 0.000382 (26/68038). AF 95% confidence interval is 0.000267. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
INSR	NM_000208.4 linkuse as main transcript	c.2665C>T	p.Arg889Trp	missense_variant	13/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3 linkuse as main transcript	c.2629C>T	p.Arg877Trp	missense_variant	12/21		NP_001073285.1
INSR	XM_011527988.3 linkuse as main transcript	c.2665C>T	p.Arg889Trp	missense_variant	13/22		XP_011526290.2
INSR	XM_011527989.4 linkuse as main transcript	c.2629C>T	p.Arg877Trp	missense_variant	12/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10 linkuse as main transcript	c.2665C>T	p.Arg889Trp	missense_variant	13/22	1	NM_000208.4	ENSP00000303830	A2	P06213-1
INSR	ENST00000341500.9 linkuse as main transcript	c.2629C>T	p.Arg877Trp	missense_variant	12/21	1		ENSP00000342838	P3	P06213-2
INSR	ENST00000597211.1 linkuse as main transcript	n.348C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000171

AC:

AN:

251470

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000325

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000306

AC:

447

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

211

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000381

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000348

Hom.:

Bravo

AF:

0.000246

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2021	Identified in a non-obese pregnant woman with a diabetes and reported as a variant of uncertain significance in published literature (Zubkova et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30663027, 27535533) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 14, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2015	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Leprechaunism syndrome;C0271695:Rabson-Mendenhall syndrome;C0342278:Insulin-resistant diabetes mellitus AND acanthosis nigricans;C1864952:Hyperinsulinism due to INSR deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

INSR-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2023

The INSR c.2665C>T variant is predicted to result in the amino acid substitution p.Arg889Trp. This variant was reported as a variant of uncertain significance in an individual with gestational diabetes (Zubkova et al. 2019. PubMed ID: 30663027). This variant is reported in 0.034% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-7141705-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;D

Eigen

Benign

0.044

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.9

.;L

MutationTaster

Benign

0.85

N;N

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.3

D;D

REVEL

Benign

0.11

Sift

Uncertain

0.019

D;D

Sift4G

Benign

0.066

T;T

Polyphen

0.31

B;B

Vest4

0.21

MVP

0.85

MPC

0.79

ClinPred

0.11

GERP RS

4.5

Varity_R

0.30

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: 10

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