rs8103483

chr19-7145363-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000208.4(INSR):c.2268-2273G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 151,716 control chromosomes in the GnomAD database, including 13,423 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (13423 hom., cov: 32)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.819

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.2268-2273G>A		intron_variant		ENST00000302850.10
INSR	NM_001079817.3	c.2232-2273G>A		intron_variant
INSR	XM_011527988.3	c.2268-2273G>A		intron_variant
INSR	XM_011527989.4	c.2232-2273G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.2268-2273G>A		intron_variant		1	NM_000208.4	A2
INSR	ENST00000341500.9	c.2232-2273G>A		intron_variant		1		P3

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60744 AN: 151596 Hom.: 13423 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.0878

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.406

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.400 AC: 60755 AN: 151716 Hom.: 13423 Cov.: 32 AF XY: 0.397 AC XY: 29454 AN XY: 74116

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.355

Gnomad4 ASJ AF: 0.415

Gnomad4 EAS AF: 0.0874

Gnomad4 SAS AF: 0.466

Gnomad4 FIN AF: 0.501

Gnomad4 NFE AF: 0.506

Gnomad4 OTH AF: 0.407

Alfa AF: 0.482 Hom.: 24353

Bravo AF: 0.381

Asia WGS AF: 0.319 AC: 1109 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.039
Dann	Benign	0.83

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: rs8103483; hg19: chr19-7145374;