rs3786681

Variant names:

• chr19-7168922-A-G
• rs3786681
• NM_000208.4:c.1484-828T>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.1484-828T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 152,030 control chromosomes in the GnomAD database, including 4,554 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 0.24 (4554 hom., cov: 32)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0300
• Publications: 6 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.1484-828T>C		intron_variant	Intron 6 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.1484-828T>C		intron_variant	Intron 6 of 20		NP_001073285.1
INSR	XM_011527988.3	c.1484-828T>C		intron_variant	Intron 6 of 21		XP_011526290.2
INSR	XM_011527989.4	c.1484-828T>C		intron_variant	Intron 6 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.1484-828T>C		intron_variant	Intron 6 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.1484-828T>C		intron_variant	Intron 6 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.1459-828T>C		intron_variant	Intron 6 of 9	1

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36847 AN: 151912 Hom.: 4544 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.279

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

GnomAD4 genome AF: 0.243 AC: 36892 AN: 152030 Hom.: 4554 Cov.: 32 AF XY: 0.247 AC XY: 18367 AN XY: 74306

African (AFR) AF: 0.208 AC: 8638 AN: 41490

American (AMR) AF: 0.244 AC: 3726 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1139 AN: 3468

East Asian (EAS) AF: 0.261 AC: 1343 AN: 5154

South Asian (SAS) AF: 0.266 AC: 1285 AN: 4824

European-Finnish (FIN) AF: 0.331 AC: 3489 AN: 10546

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.242 AC: 16447 AN: 67966

Other (OTH) AF: 0.280 AC: 592 AN: 2114

Alfa AF: 0.245 Hom.: 17712

Bravo AF: 0.233

Asia WGS AF: 0.285 AC: 990 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.60
PhyloP100		0.030
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: rs3786681; hg19: chr19-7168933;