rs7248939

Positions:

• chr19-7268427-G-A
• chr19-7268427-G-C
• chr19-7268427-G-T

Variant summary

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

The NM_000208.4(INSR):​c.101-531C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 984,182 control chromosomes in the GnomAD database, including 61,881 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 0.37 (10586 hom., cov: 30)
  • Exomes 𝑓: 0.35 (51295 hom.)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05

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]

INSR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.101-531C>T		intron_variant		ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.101-531C>T		intron_variant			NP_001073285.1
INSR	XM_011527988.3	c.101-531C>T		intron_variant			XP_011526290.2
INSR	XM_011527989.4	c.101-531C>T		intron_variant			XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.101-531C>T		intron_variant		1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.101-531C>T		intron_variant		1		ENSP00000342838.4
INSR	ENST00000598216.1	n.76-531C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.369 AC: 55921 AN: 151616 Hom.: 10563 Cov.: 30

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.361

GnomAD4 exome AF: 0.349 AC: 290608 AN: 832448 Hom.: 51295 Cov.: 29 AF XY: 0.348 AC XY: 133756 AN XY: 384424

Gnomad4 AFR exome AF: 0.393

Gnomad4 AMR exome AF: 0.387

Gnomad4 ASJ exome AF: 0.274

Gnomad4 EAS exome AF: 0.605

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.351

Gnomad4 NFE exome AF: 0.347

Gnomad4 OTH exome AF: 0.357

GnomAD4 genome AF: 0.369 AC: 55978 AN: 151734 Hom.: 10586 Cov.: 30 AF XY: 0.370 AC XY: 27406 AN XY: 74130

Gnomad4 AFR AF: 0.392

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.288

Gnomad4 EAS AF: 0.605

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.346

Gnomad4 OTH AF: 0.367

Alfa AF: 0.348 Hom.: 4915

Bravo AF: 0.371

Asia WGS AF: 0.503 AC: 1749 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.074
DANN	Benign	0.47

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: rs7248939; hg19: chr19-7268438;