rs17253937

Variant names:

• chr19-7184790-C-T
• rs17253937
• NM_000208.4:c.653-153G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000208.4(INSR):​c.653-153G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 146,896 control chromosomes in the GnomAD database, including 1,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.15 (1853 hom., cov: 32)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.875
• Publications: 15 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-7184790-C-T is Benign according to our data. Variant chr19-7184790-C-T is described in ClinVar as Benign. ClinVar VariationId is 1246416.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.653-153G>A		intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.653-153G>A		intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.653-153G>A		intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.653-153G>A		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.653-153G>A		intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.653-153G>A		intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.628-153G>A		intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes AF: 0.146 AC: 21482 AN: 146778 Hom.: 1853 Cov.: 32

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.0896

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.144

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.177

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

GnomAD4 genome AF: 0.146 AC: 21482 AN: 146896 Hom.: 1853 Cov.: 32 AF XY: 0.151 AC XY: 10803 AN XY: 71366

African (AFR) AF: 0.0417 AC: 1709 AN: 40964

American (AMR) AF: 0.201 AC: 2868 AN: 14280

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 676 AN: 3362

East Asian (EAS) AF: 0.125 AC: 630 AN: 5038

South Asian (SAS) AF: 0.221 AC: 1018 AN: 4610

European-Finnish (FIN) AF: 0.246 AC: 2343 AN: 9530

Middle Eastern (MID) AF: 0.139 AC: 40 AN: 288

European-Non Finnish (NFE) AF: 0.178 AC: 11763 AN: 65928

Other (OTH) AF: 0.177 AC: 356 AN: 2014

Alfa AF: 0.166 Hom.: 7046

Bravo AF: 0.134

Asia WGS AF: 0.167 AC: 579 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.5
DANN	Benign	0.44
PhyloP100		0.88
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: rs17253937; hg19: chr19-7184801;