chr19-7199330-G-A

Variant names:

• chr19-7199330-G-A
• rs7254358
• NM_000208.4:c.653-14693C>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.653-14693C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 151,862 control chromosomes in the GnomAD database, including 10,823 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 0.37 (10823 hom., cov: 30)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.250
• Publications: 5 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

ENSG00000303888 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.653-14693C>T		intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.653-14693C>T		intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.653-14693C>T		intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.653-14693C>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.653-14693C>T		intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56560 AN: 151744 Hom.: 10813 Cov.: 30

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.367

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

GnomAD4 genome AF: 0.373 AC: 56573 AN: 151862 Hom.: 10823 Cov.: 30 AF XY: 0.375 AC XY: 27837 AN XY: 74186

African (AFR) AF: 0.265 AC: 10952 AN: 41394

American (AMR) AF: 0.411 AC: 6258 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1476 AN: 3468

East Asian (EAS) AF: 0.453 AC: 2342 AN: 5172

South Asian (SAS) AF: 0.295 AC: 1420 AN: 4820

European-Finnish (FIN) AF: 0.498 AC: 5245 AN: 10526

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.406 AC: 27564 AN: 67940

Other (OTH) AF: 0.363 AC: 764 AN: 2104

Alfa AF: 0.390 Hom.: 32849

Bravo AF: 0.364

Asia WGS AF: 0.327 AC: 1136 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	14
DANN	Benign	0.89
PhyloP100		0.25
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: rs7254358; hg19: chr19-7199341;