rs267607184

chr19-7172381-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_000208.4(INSR):c.1177G>A(p.Gly393Arg) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G393G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: INSR NM_000208.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.56

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 8 ACMG points.

• 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, 0.994
• PP5: Variant 19-7172381-C-T is Pathogenic according to our data. Variant chr19-7172381-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14681.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.1177G>A	p.Gly393Arg	missense_variant	5/22	ENST00000302850.10
INSR	NM_001079817.3	c.1177G>A	p.Gly393Arg	missense_variant	5/21
INSR	XM_011527988.3	c.1177G>A	p.Gly393Arg	missense_variant	5/22
INSR	XM_011527989.4	c.1177G>A	p.Gly393Arg	missense_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.1177G>A	p.Gly393Arg	missense_variant	5/22	1	NM_000208.4	A2
INSR	ENST00000341500.9	c.1177G>A	p.Gly393Arg	missense_variant	5/21	1		P3
INSR	ENST00000598216.1	n.1152G>A		non_coding_transcript_exon_variant	5/10	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Leprechaunism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 05, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.1	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.97		Gain of MoRF binding (P = 0.0261);Gain of MoRF binding (P = 0.0261);
MVP		0.98
MPC		2.0
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607184; hg19: chr19-7172392;