rs11671975

Variant names:

• chr19-7177269-A-G
• rs11671975
• NM_000208.4:c.975-2538T>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.975-2538T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 152,044 control chromosomes in the GnomAD database, including 3,513 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 0.20 (3513 hom., cov: 31)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.971
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.975-2538T>C		intron_variant	Intron 3 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.975-2538T>C		intron_variant	Intron 3 of 20		NP_001073285.1
INSR	XM_011527988.3	c.975-2538T>C		intron_variant	Intron 3 of 21		XP_011526290.2
INSR	XM_011527989.4	c.975-2538T>C		intron_variant	Intron 3 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.975-2538T>C		intron_variant	Intron 3 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.975-2538T>C		intron_variant	Intron 3 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.950-2538T>C		intron_variant	Intron 3 of 9	1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31004 AN: 151924 Hom.: 3508 Cov.: 31

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.246

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

GnomAD4 genome AF: 0.204 AC: 31014 AN: 152044 Hom.: 3513 Cov.: 31 AF XY: 0.208 AC XY: 15426 AN XY: 74306

African (AFR) AF: 0.103 AC: 4290 AN: 41530

American (AMR) AF: 0.234 AC: 3563 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1072 AN: 3472

East Asian (EAS) AF: 0.151 AC: 778 AN: 5162

South Asian (SAS) AF: 0.252 AC: 1210 AN: 4810

European-Finnish (FIN) AF: 0.307 AC: 3234 AN: 10538

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16134 AN: 67980

Other (OTH) AF: 0.245 AC: 518 AN: 2110

Alfa AF: 0.234 Hom.: 5368

Bravo AF: 0.193

Asia WGS AF: 0.199 AC: 693 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.62
PhyloP100		-0.97
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: rs11671975; hg19: chr19-7177280;