rs3815901

chr19-7166530-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000208.4(INSR):c.1611-126T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,020,650 control chromosomes in the GnomAD database, including 108,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.50 (19646 hom., cov: 32)
  • Exomes 𝑓: 0.44 (88474 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.403

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-7166530-A-G is Benign according to our data. Variant chr19-7166530-A-G is described in ClinVar as [Benign]. Clinvar id is 1231520.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.1611-126T>C		intron_variant		ENST00000302850.10
INSR	NM_001079817.3	c.1611-126T>C		intron_variant
INSR	XM_011527988.3	c.1611-126T>C		intron_variant
INSR	XM_011527989.4	c.1611-126T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.1611-126T>C		intron_variant		1	NM_000208.4	A2
INSR	ENST00000341500.9	c.1611-126T>C		intron_variant		1		P3
INSR	ENST00000598216.1	n.1586-126T>C		intron_variant, non_coding_transcript_variant		1
INSR	ENST00000600492.1	c.12-126T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75831 AN: 151884 Hom.: 19601 Cov.: 32

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.530

GnomAD4 exome AF: 0.443 AC: 385118 AN: 868648 Hom.: 88474 AF XY: 0.447 AC XY: 199564 AN XY: 446248

Gnomad4 AFR exome AF: 0.644

Gnomad4 AMR exome AF: 0.400

Gnomad4 ASJ exome AF: 0.545

Gnomad4 EAS exome AF: 0.287

Gnomad4 SAS exome AF: 0.543

Gnomad4 FIN exome AF: 0.448

Gnomad4 NFE exome AF: 0.431

Gnomad4 OTH exome AF: 0.465

GnomAD4 genome AF: 0.499 AC: 75920 AN: 152002 Hom.: 19646 Cov.: 32 AF XY: 0.499 AC XY: 37106 AN XY: 74298

Gnomad4 AFR AF: 0.645

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.537

Gnomad4 EAS AF: 0.323

Gnomad4 SAS AF: 0.550

Gnomad4 FIN AF: 0.466

Gnomad4 NFE AF: 0.437

Gnomad4 OTH AF: 0.535

Alfa AF: 0.494 Hom.: 2834

Bravo AF: 0.501

Asia WGS AF: 0.518 AC: 1803 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.79
Dann	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3815901; hg19: chr19-7166541; COSMIC: COSV57172887;