rs8108622

Variant names:

• chr19-7182742-T-A
• rs8108622
• NM_000208.4:c.974+1574A>T

Your query was ambiguous. Multiple possible variants found:

• chr19-7182742-T-A
• chr19-7182742-T-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.974+1574A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 151,762 control chromosomes in the GnomAD database, including 4,124 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 0.23 (4124 hom., cov: 30)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.869
• Publications: 11 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.974+1574A>T		intron_variant	Intron 3 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.974+1574A>T		intron_variant	Intron 3 of 20		NP_001073285.1
INSR	XM_011527988.3	c.974+1574A>T		intron_variant	Intron 3 of 21		XP_011526290.2
INSR	XM_011527989.4	c.974+1574A>T		intron_variant	Intron 3 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.974+1574A>T		intron_variant	Intron 3 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.974+1574A>T		intron_variant	Intron 3 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.949+1574A>T		intron_variant	Intron 3 of 9	1

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35346 AN: 151644 Hom.: 4117 Cov.: 30

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.256

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

GnomAD4 genome AF: 0.233 AC: 35379 AN: 151762 Hom.: 4124 Cov.: 30 AF XY: 0.236 AC XY: 17501 AN XY: 74150

African (AFR) AF: 0.233 AC: 9652 AN: 41368

American (AMR) AF: 0.242 AC: 3676 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1030 AN: 3468

East Asian (EAS) AF: 0.147 AC: 760 AN: 5170

South Asian (SAS) AF: 0.231 AC: 1111 AN: 4810

European-Finnish (FIN) AF: 0.306 AC: 3222 AN: 10514

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.223 AC: 15174 AN: 67916

Other (OTH) AF: 0.256 AC: 537 AN: 2100

Alfa AF: 0.128 Hom.: 214

Bravo AF: 0.229

Asia WGS AF: 0.200 AC: 695 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.53
DANN	Benign	0.46
PhyloP100		-0.87
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: rs8108622; hg19: chr19-7182753;