rs891087

Positions:

• chr19-7184507-G-A
• chr19-7184507-G-C
• chr19-7184507-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000208.4(INSR):​c.783C>T​(p.Asp261=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0972 in 1,613,664 control chromosomes in the GnomAD database, including 8,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1311 hom., cov: 30)
  • Exomes 𝑓: 0.095 (7511 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.90

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-7184507-G-A is Benign according to our data. Variant chr19-7184507-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 330475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.9 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.783C>T	p.Asp261=	synonymous_variant	3/22	ENST00000302850.10
INSR	NM_001079817.3	c.783C>T	p.Asp261=	synonymous_variant	3/21
INSR	XM_011527988.3	c.783C>T	p.Asp261=	synonymous_variant	3/22
INSR	XM_011527989.4	c.783C>T	p.Asp261=	synonymous_variant	3/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.783C>T	p.Asp261=	synonymous_variant	3/22	1	NM_000208.4	A2
INSR	ENST00000341500.9	c.783C>T	p.Asp261=	synonymous_variant	3/21	1		P3
INSR	ENST00000598216.1	n.758C>T		non_coding_transcript_exon_variant	3/10	1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 17993 AN: 151774 Hom.: 1303 Cov.: 30

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.0789

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.0422

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.0727

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0887

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.0973 AC: 24425 AN: 251000 Hom.: 1470 AF XY: 0.101 AC XY: 13666 AN XY: 135736

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.0579

Gnomad ASJ exome AF: 0.0506

Gnomad EAS exome AF: 0.0406

Gnomad SAS exome AF: 0.183

Gnomad FIN exome AF: 0.0780

Gnomad NFE exome AF: 0.0881

Gnomad OTH exome AF: 0.0942

GnomAD4 exome AF: 0.0949 AC: 138791 AN: 1461772 Hom.: 7511 Cov.: 33 AF XY: 0.0970 AC XY: 70513 AN XY: 727180

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.0606

Gnomad4 ASJ exome AF: 0.0510

Gnomad4 EAS exome AF: 0.0532

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.0766

Gnomad4 NFE exome AF: 0.0898

Gnomad4 OTH exome AF: 0.0983

GnomAD4 genome AF: 0.119 AC: 18029 AN: 151892 Hom.: 1311 Cov.: 30 AF XY: 0.119 AC XY: 8795 AN XY: 74214

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.0787

Gnomad4 ASJ AF: 0.0550

Gnomad4 EAS AF: 0.0421

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.0727

Gnomad4 NFE AF: 0.0887

Gnomad4 OTH AF: 0.117

Alfa AF: 0.0889 Hom.: 497

Bravo AF: 0.121

Asia WGS AF: 0.167 AC: 578 AN: 3478

EpiCase AF: 0.0885

EpiControl AF: 0.0873

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 26, 2018

- -

Leprechaunism syndrome;C0271695:Rabson-Mendenhall syndrome;C0342278:Insulin-resistant diabetes mellitus AND acanthosis nigricans;C1864952:Hyperinsulinism due to INSR deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Rabson-Mendenhall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Leprechaunism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.8
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs891087; hg19: chr19-7184518; COSMIC: COSV57161309;