rs7248104

Variant names:

• chr19-7224420-G-A
• rs7248104
• NM_000208.4:c.653-39783C>T

Variant summary

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

The NM_000208.4(INSR):​c.653-39783C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 151,712 control chromosomes in the GnomAD database, including 11,241 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 0.38 (11241 hom., cov: 30)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 87 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=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.653-39783C>T		intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.653-39783C>T		intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.653-39783C>T		intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.653-39783C>T		intron_variant	Intron 2 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.653-39783C>T		intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.653-39783C>T		intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.628-39783C>T		intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57485 AN: 151594 Hom.: 11240 Cov.: 30

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.381

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

GnomAD4 genome AF: 0.379 AC: 57510 AN: 151712 Hom.: 11241 Cov.: 30 AF XY: 0.382 AC XY: 28293 AN XY: 74124

African (AFR) AF: 0.306 AC: 12630 AN: 41338

American (AMR) AF: 0.375 AC: 5713 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1577 AN: 3472

East Asian (EAS) AF: 0.316 AC: 1625 AN: 5146

South Asian (SAS) AF: 0.414 AC: 1997 AN: 4820

European-Finnish (FIN) AF: 0.457 AC: 4785 AN: 10472

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27980 AN: 67936

Other (OTH) AF: 0.377 AC: 790 AN: 2098

Alfa AF: 0.402 Hom.: 48056

Bravo AF: 0.370

Asia WGS AF: 0.365 AC: 1268 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.4
DANN	Benign	0.73
PhyloP100		1.1
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: rs7248104; hg19: chr19-7224431;