rs121913157

chr19-7120739-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.54

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Protein kinase (size 275) in uniprot entity INSR_HUMAN there are 19 pathogenic changes around while only 4 benign (83%) in NM_000208.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, INSR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.3540G>A	p.Met1180Ile	missense_variant	20/22	ENST00000302850.10
INSR	NM_001079817.3	c.3504G>A	p.Met1168Ile	missense_variant	19/21
INSR	XM_011527988.3	c.3537G>A	p.Met1179Ile	missense_variant	20/22
INSR	XM_011527989.4	c.3501G>A	p.Met1167Ile	missense_variant	19/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.3540G>A	p.Met1180Ile	missense_variant	20/22	1	NM_000208.4	A2
INSR	ENST00000341500.9	c.3504G>A	p.Met1168Ile	missense_variant	19/21	1		P3
INSR	ENST00000601099.1	n.451G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Insulin resistance Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 07, 1994

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2021

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"). 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. Experimental studies have shown that this missense change affects INSR function (PMID: 1314826, 1890161). ClinVar contains an entry for this variant (Variation ID: 14709). This variant is also known as p.Met1153Ile. This missense change has been observed in individual(s) with INSR-related conditions (PMID: 1890161). This variant is not present in population databases (ExAC no frequency). 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. -

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
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
MutationTaster	Benign	1.0	A;A
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

Other links and lift over

dbSNP: rs121913157; hg19: chr19-7120750;