chr19-7125508-G-A

Position:

• chr19-7125508-G-A

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.3033C>T​(p.Tyr1011=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,613,762 control chromosomes in the GnomAD database, including 3,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (222 hom., cov: 31)
  • Exomes 𝑓: 0.061 (3187 hom.)
• Consequence: INSR NM_000208.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.587

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=-0.6).
• BP6: Variant 19-7125508-G-A is Benign according to our data. Variant chr19-7125508-G-A is described in ClinVar as [Benign]. Clinvar id is 330447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7125508-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.587 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.3033C>T	p.Tyr1011=	synonymous_variant	17/22	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.2997C>T	p.Tyr999=	synonymous_variant	16/21		NP_001073285.1
INSR	XM_011527988.3	c.3030C>T	p.Tyr1010=	synonymous_variant	17/22		XP_011526290.2
INSR	XM_011527989.4	c.2994C>T	p.Tyr998=	synonymous_variant	16/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.3033C>T	p.Tyr1011=	synonymous_variant	17/22	1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.2997C>T	p.Tyr999=	synonymous_variant	16/21	1		ENSP00000342838	P3

Frequencies

GnomAD3 genomes AF: 0.0464 AC: 7056 AN: 152126 Hom.: 222 Cov.: 31

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0403

Gnomad ASJ AF: 0.0827

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.0720

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0678

Gnomad OTH AF: 0.0617

GnomAD3 exomes AF: 0.0505 AC: 12672 AN: 251024 Hom.: 429 AF XY: 0.0517 AC XY: 7016 AN XY: 135676

Gnomad AFR exome AF: 0.00978

Gnomad AMR exome AF: 0.0379

Gnomad ASJ exome AF: 0.0800

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0188

Gnomad FIN exome AF: 0.0717

Gnomad NFE exome AF: 0.0695

Gnomad OTH exome AF: 0.0640

GnomAD4 exome AF: 0.0613 AC: 89639 AN: 1461518 Hom.: 3187 Cov.: 34 AF XY: 0.0605 AC XY: 43964 AN XY: 727052

Gnomad4 AFR exome AF: 0.0117

Gnomad4 AMR exome AF: 0.0395

Gnomad4 ASJ exome AF: 0.0792

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0196

Gnomad4 FIN exome AF: 0.0708

Gnomad4 NFE exome AF: 0.0683

Gnomad4 OTH exome AF: 0.0576

GnomAD4 genome AF: 0.0463 AC: 7052 AN: 152244 Hom.: 222 Cov.: 31 AF XY: 0.0467 AC XY: 3474 AN XY: 74416

Gnomad4 AFR AF: 0.0115

Gnomad4 AMR AF: 0.0402

Gnomad4 ASJ AF: 0.0827

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0165

Gnomad4 FIN AF: 0.0720

Gnomad4 NFE AF: 0.0678

Gnomad4 OTH AF: 0.0615

Alfa AF: 0.0591 Hom.: 207

Bravo AF: 0.0431

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0722

EpiControl AF: 0.0760

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 01, 2019

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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 12, 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	-0.60
CADD	Benign	7.5
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs1799815; hg19: chr19-7125519; COSMIC: COSV57162917; COSMIC: COSV57162917;