rs891088

Positions:

• chr19-7184751-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.653-114T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 777,212 control chromosomes in the GnomAD database, including 34,904 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (8511 hom., cov: 32)
  • Exomes 𝑓: 0.27 (26393 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.725

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=-0.87).
• BP6: Variant 19-7184751-A-G is Benign according to our data. Variant chr19-7184751-A-G is described in ClinVar as [Benign]. Clinvar id is 1286680.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.653-114T>C		intron_variant		ENST00000302850.10
INSR	NM_001079817.3	c.653-114T>C		intron_variant
INSR	XM_011527988.3	c.653-114T>C		intron_variant
INSR	XM_011527989.4	c.653-114T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.653-114T>C		intron_variant		1	NM_000208.4	A2
INSR	ENST00000341500.9	c.653-114T>C		intron_variant		1		P3
INSR	ENST00000598216.1	n.628-114T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48828 AN: 151888 Hom.: 8479 Cov.: 32

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.326

GnomAD4 exome AF: 0.271 AC: 169620 AN: 625206 Hom.: 26393 AF XY: 0.273 AC XY: 86678 AN XY: 317048

Gnomad4 AFR exome AF: 0.471

Gnomad4 AMR exome AF: 0.296

Gnomad4 ASJ exome AF: 0.240

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.463

Gnomad4 FIN exome AF: 0.287

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.291

GnomAD4 genome AF: 0.322 AC: 48908 AN: 152006 Hom.: 8511 Cov.: 32 AF XY: 0.324 AC XY: 24075 AN XY: 74306

Gnomad4 AFR AF: 0.449

Gnomad4 AMR AF: 0.290

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.399

Gnomad4 FIN AF: 0.294

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.333

Alfa AF: 0.274 Hom.: 13851

Bravo AF: 0.324

Asia WGS AF: 0.372 AC: 1289 AN: 3470

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	-0.87
CADD	Benign	1.7
DANN	Benign	0.57

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: rs891088; hg19: chr19-7184762;