chr19-7239544-A-G

Variant names:

• chr19-7239544-A-G
• rs3852876
• NM_000208.4:c.652+27801T>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.652+27801T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 151,946 control chromosomes in the GnomAD database, including 10,100 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 0.34 (10100 hom., cov: 31)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350
• Publications: 10 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.652+27801T>C		intron_variant	Intron 2 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.652+27801T>C		intron_variant	Intron 2 of 20		NP_001073285.1
INSR	XM_011527988.3	c.652+27801T>C		intron_variant	Intron 2 of 21		XP_011526290.2
INSR	XM_011527989.4	c.652+27801T>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.652+27801T>C		intron_variant	Intron 2 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.652+27801T>C		intron_variant	Intron 2 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.627+27801T>C		intron_variant	Intron 2 of 9	1

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52329 AN: 151828 Hom.: 10082 Cov.: 31

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.325

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

GnomAD4 genome AF: 0.345 AC: 52385 AN: 151946 Hom.: 10100 Cov.: 31 AF XY: 0.339 AC XY: 25206 AN XY: 74270

African (AFR) AF: 0.514 AC: 21281 AN: 41422

American (AMR) AF: 0.252 AC: 3841 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1041 AN: 3468

East Asian (EAS) AF: 0.187 AC: 966 AN: 5168

South Asian (SAS) AF: 0.198 AC: 956 AN: 4824

European-Finnish (FIN) AF: 0.274 AC: 2895 AN: 10552

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20228 AN: 67966

Other (OTH) AF: 0.321 AC: 679 AN: 2112

Alfa AF: 0.315 Hom.: 25219

Bravo AF: 0.354

Asia WGS AF: 0.195 AC: 684 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.57
PhyloP100		0.035
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: rs3852876; hg19: chr19-7239555;