rs4804416

Variant names:

• chr19-7223837-T-G
• rs4804416
• NM_000208.4:c.653-39200A>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.653-39200A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 151,994 control chromosomes in the GnomAD database, including 10,844 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 (10844 hom., cov: 31)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.342
• Publications: 41 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.653-39200A>C		intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.653-39200A>C		intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.653-39200A>C		intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.653-39200A>C		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.653-39200A>C		intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.653-39200A>C		intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.628-39200A>C		intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55757 AN: 151876 Hom.: 10830 Cov.: 31

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.377

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

GnomAD4 genome AF: 0.367 AC: 55794 AN: 151994 Hom.: 10844 Cov.: 31 AF XY: 0.363 AC XY: 26974 AN XY: 74256

African (AFR) AF: 0.246 AC: 10206 AN: 41466

American (AMR) AF: 0.418 AC: 6371 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1201 AN: 3466

East Asian (EAS) AF: 0.389 AC: 2007 AN: 5162

South Asian (SAS) AF: 0.299 AC: 1439 AN: 4814

European-Finnish (FIN) AF: 0.381 AC: 4015 AN: 10540

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.431 AC: 29312 AN: 67986

Other (OTH) AF: 0.374 AC: 789 AN: 2112

Alfa AF: 0.410 Hom.: 51988

Bravo AF: 0.366

Asia WGS AF: 0.288 AC: 1004 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.3
DANN	Benign	0.71
PhyloP100		0.34
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: rs4804416; hg19: chr19-7223848;