rs10411676

Variant names:

• chr19-7273980-A-G
• rs10411676
• NM_000208.4:c.101-6084T>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.101-6084T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 151,640 control chromosomes in the GnomAD database, including 12,064 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 0.39 (12064 hom., cov: 28)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.170
• Publications: 6 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.101-6084T>C		intron_variant	Intron 1 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.101-6084T>C		intron_variant	Intron 1 of 20		NP_001073285.1
INSR	XM_011527988.3	c.101-6084T>C		intron_variant	Intron 1 of 21		XP_011526290.2
INSR	XM_011527989.4	c.101-6084T>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.101-6084T>C		intron_variant	Intron 1 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.101-6084T>C		intron_variant	Intron 1 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.76-6084T>C		intron_variant	Intron 1 of 9	1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59797 AN: 151522 Hom.: 12047 Cov.: 28

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.395 AC: 59837 AN: 151640 Hom.: 12064 Cov.: 28 AF XY: 0.391 AC XY: 28932 AN XY: 74072

African (AFR) AF: 0.382 AC: 15792 AN: 41368

American (AMR) AF: 0.425 AC: 6465 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 1590 AN: 3470

East Asian (EAS) AF: 0.139 AC: 709 AN: 5106

South Asian (SAS) AF: 0.274 AC: 1315 AN: 4798

European-Finnish (FIN) AF: 0.357 AC: 3758 AN: 10514

Middle Eastern (MID) AF: 0.421 AC: 123 AN: 292

European-Non Finnish (NFE) AF: 0.427 AC: 29007 AN: 67870

Other (OTH) AF: 0.372 AC: 785 AN: 2110

Alfa AF: 0.419 Hom.: 52256

Bravo AF: 0.401

Asia WGS AF: 0.236 AC: 823 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.12
DANN	Benign	0.31
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10411676; hg19: chr19-7273991;