rs1051690

Positions:

• chr19-7116952-T-C
• chr19-7116952-T-G

Variant summary

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

The NM_000208.4(INSR):​c.*104A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.847 in 920,464 control chromosomes in the GnomAD database, including 331,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (53240 hom., cov: 29)
  • Exomes 𝑓: 0.85 (278091 hom.)
• Consequence: INSR NM_000208.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.550

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=-0.85).
• BP6: Variant 19-7116952-T-C is Benign according to our data. Variant chr19-7116952-T-C is described in ClinVar as [Benign]. Clinvar id is 330436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.*104A>G		3_prime_UTR_variant	22/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.*104A>G		3_prime_UTR_variant	21/21		NP_001073285.1
INSR	XM_011527988.3	c.*104A>G		3_prime_UTR_variant	22/22		XP_011526290.2
INSR	XM_011527989.4	c.*104A>G		3_prime_UTR_variant	21/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.*104A>G		3_prime_UTR_variant	22/22	1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.*104A>G		3_prime_UTR_variant	21/21	1		ENSP00000342838	P3

Frequencies

GnomAD3 genomes AF: 0.837 AC: 127054 AN: 151830 Hom.: 53192 Cov.: 29

Gnomad AFR AF: 0.817

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.888

Gnomad EAS AF: 0.954

Gnomad SAS AF: 0.914

Gnomad FIN AF: 0.772

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.855

GnomAD4 exome AF: 0.849 AC: 652733 AN: 768516 Hom.: 278091 Cov.: 10 AF XY: 0.852 AC XY: 348143 AN XY: 408440

Gnomad4 AFR exome AF: 0.821

Gnomad4 AMR exome AF: 0.925

Gnomad4 ASJ exome AF: 0.890

Gnomad4 EAS exome AF: 0.955

Gnomad4 SAS exome AF: 0.910

Gnomad4 FIN exome AF: 0.774

Gnomad4 NFE exome AF: 0.833

Gnomad4 OTH exome AF: 0.850

GnomAD4 genome AF: 0.837 AC: 127159 AN: 151948 Hom.: 53240 Cov.: 29 AF XY: 0.838 AC XY: 62203 AN XY: 74244

Gnomad4 AFR AF: 0.817

Gnomad4 AMR AF: 0.892

Gnomad4 ASJ AF: 0.888

Gnomad4 EAS AF: 0.954

Gnomad4 SAS AF: 0.914

Gnomad4 FIN AF: 0.772

Gnomad4 NFE AF: 0.829

Gnomad4 OTH AF: 0.858

Alfa AF: 0.839 Hom.: 59229

Bravo AF: 0.845

Asia WGS AF: 0.935 AC: 3250 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 23315997, 20971123, 18192692) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Rabson-Mendenhall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 15, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Leprechaunism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.32

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: rs1051690; hg19: chr19-7116963; COSMIC: COSV105137620; COSMIC: COSV105137620;