rs919275

chr19-7261430-T-C

Variant summary

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

The NM_000208.4(INSR):c.652+5915A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 152,058 control chromosomes in the GnomAD database, including 19,762 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 0.48 (19762 hom., cov: 32)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.613

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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.652+5915A>G		intron_variant		ENST00000302850.10
INSR	NM_001079817.3	c.652+5915A>G		intron_variant
INSR	XM_011527988.3	c.652+5915A>G		intron_variant
INSR	XM_011527989.4	c.652+5915A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.652+5915A>G		intron_variant		1	NM_000208.4	A2
INSR	ENST00000341500.9	c.652+5915A>G		intron_variant		1		P3
INSR	ENST00000598216.1	n.627+5915A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73181 AN: 151940 Hom.: 19723 Cov.: 32

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.488

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

GnomAD4 genome AF: 0.482 AC: 73254 AN: 152058 Hom.: 19762 Cov.: 32 AF XY: 0.471 AC XY: 35039 AN XY: 74316

Gnomad4 AFR AF: 0.739

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.496

Gnomad4 EAS AF: 0.232

Gnomad4 SAS AF: 0.319

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.403

Gnomad4 OTH AF: 0.481

Alfa AF: 0.422 Hom.: 18275

Bravo AF: 0.503

Asia WGS AF: 0.299 AC: 1042 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.88
Dann	Benign	0.40

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: rs919275; hg19: chr19-7261441;