19-7120739-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_000208.4(INSR):​c.3540G>A​(p.Met1180Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

INSR
NM_000208.4 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 7.54
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a domain Protein kinase (size 275) in uniprot entity INSR_HUMAN there are 25 pathogenic changes around while only 5 benign (83%) in NM_000208.4
PM2
Very rare variant in population databases, with high coverage;
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
INSRNM_000208.4 linkc.3540G>A p.Met1180Ile missense_variant Exon 20 of 22 ENST00000302850.10 NP_000199.2 P06213-1
INSRNM_001079817.3 linkc.3504G>A p.Met1168Ile missense_variant Exon 19 of 21 NP_001073285.1 P06213-2
INSRXM_011527988.3 linkc.3537G>A p.Met1179Ile missense_variant Exon 20 of 22 XP_011526290.2
INSRXM_011527989.4 linkc.3501G>A p.Met1167Ile missense_variant Exon 19 of 21 XP_011526291.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
INSRENST00000302850.10 linkc.3540G>A p.Met1180Ile missense_variant Exon 20 of 22 1 NM_000208.4 ENSP00000303830.4 P06213-1
INSRENST00000341500.9 linkc.3504G>A p.Met1168Ile missense_variant Exon 19 of 21 1 ENSP00000342838.4 P06213-2
INSRENST00000601099.1 linkn.451G>A non_coding_transcript_exon_variant Exon 3 of 3 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Insulin resistance Pathogenic:1
Jun 07, 1994
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Uncertain:1
Aug 23, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies have shown that this missense change affects INSR function (PMID: 1314826, 1890161). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 14709). This sequence change replaces methionine with isoleucine at codon 1180 of the INSR protein (p.Met1180Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with INSR-related conditions (PMID: 1890161). This variant is also known as p.Met1153Ile. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
.;D
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Uncertain
0.25
D
MutationAssessor
Benign
0.83
.;L
PrimateAI
Pathogenic
0.91
D
PROVEAN
Uncertain
-3.6
D;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0070
D;D
Polyphen
1.0
D;D
Vest4
0.95
MutPred
0.89
.;Gain of catalytic residue at M1180 (P = 0.0671);
MVP
0.86
MPC
1.9
ClinPred
0.99
D
GERP RS
4.5
Varity_R
0.94
gMVP
0.95

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.

Other links and lift over

dbSNP: rs121913157; hg19: chr19-7120750; API