rs12971499

chr19-7214271-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.653-29634G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 152,008 control chromosomes in the GnomAD database, including 24,232 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 0.56 (24232 hom., cov: 31)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.09

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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.653-29634G>A		intron_variant		ENST00000302850.10
INSR	NM_001079817.3	c.653-29634G>A		intron_variant
INSR	XM_011527988.3	c.653-29634G>A		intron_variant
INSR	XM_011527989.4	c.653-29634G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.653-29634G>A		intron_variant		1	NM_000208.4	A2
INSR	ENST00000341500.9	c.653-29634G>A		intron_variant		1		P3
INSR	ENST00000598216.1	n.628-29634G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85566 AN: 151890 Hom.: 24219 Cov.: 31

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.566

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

GnomAD4 genome AF: 0.563 AC: 85613 AN: 152008 Hom.: 24232 Cov.: 31 AF XY: 0.560 AC XY: 41632 AN XY: 74286

Gnomad4 AFR AF: 0.560

Gnomad4 AMR AF: 0.535

Gnomad4 ASJ AF: 0.582

Gnomad4 EAS AF: 0.428

Gnomad4 SAS AF: 0.543

Gnomad4 FIN AF: 0.543

Gnomad4 NFE AF: 0.587

Gnomad4 OTH AF: 0.561

Alfa AF: 0.584 Hom.: 23719

Bravo AF: 0.562

Asia WGS AF: 0.473 AC: 1647 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.086
Dann	Benign	0.74

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: rs12971499; hg19: chr19-7214282;