rs3815902

Positions:

• chr19-7166127-G-A
• chr19-7166127-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000302850.10(INSR):​c.1861+27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,611,992 control chromosomes in the GnomAD database, including 46,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3716 hom., cov: 31)
  • Exomes 𝑓: 0.24 (43033 hom.)
• Consequence: INSR ENST00000302850.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0550

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 19-7166127-G-A is Benign according to our data. Variant chr19-7166127-G-A is described in ClinVar as [Benign]. Clinvar id is 439832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.1861+27C>T		intron_variant		ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.1861+27C>T		intron_variant			NP_001073285.1
INSR	XM_011527988.3	c.1861+27C>T		intron_variant			XP_011526290.2
INSR	XM_011527989.4	c.1861+27C>T		intron_variant			XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.1861+27C>T		intron_variant		1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.1861+27C>T		intron_variant		1		ENSP00000342838	P3
INSR	ENST00000598216.1	n.1836+27C>T		intron_variant, non_coding_transcript_variant		1
INSR	ENST00000600492.1	c.262+27C>T		intron_variant		5		ENSP00000473170

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32199 AN: 151446 Hom.: 3712 Cov.: 31

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.250

GnomAD3 exomes AF: 0.243 AC: 61113 AN: 251342 Hom.: 7627 AF XY: 0.245 AC XY: 33225 AN XY: 135842

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.254

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.210

Gnomad SAS exome AF: 0.217

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.240 AC: 349938 AN: 1460448 Hom.: 43033 Cov.: 35 AF XY: 0.240 AC XY: 174107 AN XY: 726576

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.313

Gnomad4 EAS exome AF: 0.201

Gnomad4 SAS exome AF: 0.223

Gnomad4 FIN exome AF: 0.316

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.213 AC: 32208 AN: 151544 Hom.: 3716 Cov.: 31 AF XY: 0.217 AC XY: 16025 AN XY: 73976

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.232

Gnomad4 ASJ AF: 0.311

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.249

Alfa AF: 0.222 Hom.: 2558

Bravo AF: 0.200

Asia WGS AF: 0.229 AC: 794 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 11, 2019	- -

Rabson-Mendenhall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Leprechaunism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.4
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs3815902; hg19: chr19-7166138; COSMIC: COSV57159747;