rs7254487

Variant names:

• chr19-7269310-A-G
• rs7254487
• NM_000208.4:c.101-1414T>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.101-1414T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 149,738 control chromosomes in the GnomAD database, including 9,117 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 0.34 (9117 hom., cov: 27)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.219
• Publications: 9 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.101-1414T>C		intron_variant	Intron 1 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.101-1414T>C		intron_variant	Intron 1 of 20		NP_001073285.1
INSR	XM_011527988.3	c.101-1414T>C		intron_variant	Intron 1 of 21		XP_011526290.2
INSR	XM_011527989.4	c.101-1414T>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.101-1414T>C		intron_variant	Intron 1 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.101-1414T>C		intron_variant	Intron 1 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.76-1414T>C		intron_variant	Intron 1 of 9	1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 50497 AN: 149618 Hom.: 9101 Cov.: 27

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.321

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

GnomAD4 genome AF: 0.338 AC: 50544 AN: 149738 Hom.: 9117 Cov.: 27 AF XY: 0.338 AC XY: 24656 AN XY: 72944

African (AFR) AF: 0.417 AC: 16917 AN: 40602

American (AMR) AF: 0.233 AC: 3481 AN: 14918

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 802 AN: 3444

East Asian (EAS) AF: 0.579 AC: 2939 AN: 5072

South Asian (SAS) AF: 0.363 AC: 1720 AN: 4742

European-Finnish (FIN) AF: 0.337 AC: 3393 AN: 10070

Middle Eastern (MID) AF: 0.328 AC: 95 AN: 290

European-Non Finnish (NFE) AF: 0.297 AC: 20116 AN: 67626

Other (OTH) AF: 0.326 AC: 674 AN: 2068

Alfa AF: 0.321 Hom.: 6061

Bravo AF: 0.331

Asia WGS AF: 0.468 AC: 1622 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.3
DANN	Benign	0.52
PhyloP100		-0.22
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: rs7254487; hg19: chr19-7269321;