NM_000208.4:c.101-966T>C

Variant names:

• chr19-7268862-A-G
• rs62109585
• NM_000208.4:c.101-966T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000208.4(INSR):​c.101-966T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 151,948 control chromosomes in the GnomAD database, including 6,258 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (6258 hom., cov: 30)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• insulin-resistance syndrome type A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• hyperinsulinism due to INSR deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• Rabson-Mendenhall syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.101-966T>C		intron_variant	Intron 1 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.101-966T>C		intron_variant	Intron 1 of 20		NP_001073285.1
INSR	XM_011527988.3	c.101-966T>C		intron_variant	Intron 1 of 21		XP_011526290.2
INSR	XM_011527989.4	c.101-966T>C		intron_variant	Intron 1 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.101-966T>C		intron_variant	Intron 1 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.101-966T>C		intron_variant	Intron 1 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.76-966T>C		intron_variant	Intron 1 of 9	1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42097 AN: 151828 Hom.: 6256 Cov.: 30

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.284

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.277 AC: 42112 AN: 151948 Hom.: 6258 Cov.: 30 AF XY: 0.275 AC XY: 20442 AN XY: 74252

African (AFR) AF: 0.200 AC: 8292 AN: 41444

American (AMR) AF: 0.214 AC: 3263 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 889 AN: 3470

East Asian (EAS) AF: 0.258 AC: 1331 AN: 5168

South Asian (SAS) AF: 0.300 AC: 1449 AN: 4824

European-Finnish (FIN) AF: 0.321 AC: 3385 AN: 10554

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22361 AN: 67940

Other (OTH) AF: 0.287 AC: 606 AN: 2108

Alfa AF: 0.305 Hom.: 11852

Bravo AF: 0.263

Asia WGS AF: 0.300 AC: 1044 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.72
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs62109585; hg19: chr19-7268873;