chr19-7166127-G-A

Variant names:

• chr19-7166127-G-A
• rs3815902
• NM_000208.4:c.1861+27C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000208.4(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 NM_000208.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0550
• Publications: 18 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 -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 rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.1861+27C>T		intron_variant	Intron 8 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.1861+27C>T		intron_variant	Intron 8 of 20		NP_001073285.1
INSR	XM_011527988.3	c.1861+27C>T		intron_variant	Intron 8 of 21		XP_011526290.2
INSR	XM_011527989.4	c.1861+27C>T		intron_variant	Intron 8 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.1861+27C>T		intron_variant	Intron 8 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.1861+27C>T		intron_variant	Intron 8 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.1836+27C>T		intron_variant	Intron 8 of 9	1
INSR	ENST00000600492.1	c.262+27C>T		intron_variant	Intron 2 of 3	5		ENSP00000473170.1

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

GnomAD2 exomes AF: 0.243 AC: 61113 AN: 251342 AF XY: 0.245

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 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

African (AFR) AF: 0.115 AC: 3851 AN: 33460

American (AMR) AF: 0.250 AC: 11177 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 8188 AN: 26120

East Asian (EAS) AF: 0.201 AC: 7984 AN: 39652

South Asian (SAS) AF: 0.223 AC: 19220 AN: 86136

European-Finnish (FIN) AF: 0.316 AC: 16872 AN: 53366

Middle Eastern (MID) AF: 0.278 AC: 1601 AN: 5764

European-Non Finnish (NFE) AF: 0.240 AC: 266659 AN: 1110918

Other (OTH) AF: 0.238 AC: 14386 AN: 60324

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

African (AFR) AF: 0.120 AC: 4963 AN: 41278

American (AMR) AF: 0.232 AC: 3527 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1077 AN: 3466

East Asian (EAS) AF: 0.218 AC: 1124 AN: 5146

South Asian (SAS) AF: 0.226 AC: 1081 AN: 4782

European-Finnish (FIN) AF: 0.334 AC: 3480 AN: 10418

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.239 AC: 16217 AN: 67930

Other (OTH) AF: 0.249 AC: 525 AN: 2106

Alfa AF: 0.222 Hom.: 2774

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

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Rabson-Mendenhall syndrome Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leprechaunism syndrome Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.4
DANN	Benign	0.52
PhyloP100		-0.055
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: rs3815902; hg19: chr19-7166138; COSMIC: COSV57159747;