19-7294494-C-T

Variant names:

• chr19-7294494-C-T
• rs1864010
• NM_000208.4:c.-603G>A

Variant summary

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

The NM_000208.4(INSR):​c.-603G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.723 in 149,052 control chromosomes in the GnomAD database, including 40,347 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 0.72 (40347 hom., cov: 26)
• Consequence: INSR NM_000208.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.233
• Publications: 7 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=-0.63).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.-603G>A		upstream_gene_variant		ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.-603G>A		upstream_gene_variant			NP_001073285.1
INSR	XM_011527988.3	c.-603G>A		upstream_gene_variant			XP_011526290.2
INSR	XM_011527989.4	c.-603G>A		upstream_gene_variant			XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.-603G>A		upstream_gene_variant		1	NM_000208.4	ENSP00000303830.4

Frequencies

GnomAD3 genomes AF: 0.724 AC: 107762 AN: 148944 Hom.: 40339 Cov.: 26

Gnomad AFR AF: 0.550

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.740

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.805

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.753

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

GnomAD4 genome AF: 0.723 AC: 107801 AN: 149052 Hom.: 40347 Cov.: 26 AF XY: 0.715 AC XY: 51990 AN XY: 72704

African (AFR) AF: 0.551 AC: 22479 AN: 40824

American (AMR) AF: 0.740 AC: 11156 AN: 15082

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2641 AN: 3438

East Asian (EAS) AF: 0.467 AC: 2277 AN: 4874

South Asian (SAS) AF: 0.686 AC: 3281 AN: 4780

European-Finnish (FIN) AF: 0.724 AC: 7229 AN: 9988

Middle Eastern (MID) AF: 0.813 AC: 234 AN: 288

European-Non Finnish (NFE) AF: 0.844 AC: 56389 AN: 66824

Other (OTH) AF: 0.744 AC: 1539 AN: 2068

Alfa AF: 0.772 Hom.: 5352

Bravo AF: 0.717

Asia WGS AF: 0.532 AC: 1711 AN: 3220

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Uncertain	0.97
PhyloP100		0.23
PromoterAI		-0.18	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1864010; hg19: chr19-7294505; COSMIC: COSV57161407;