rs4804416

Positions:

• chr19-7223837-T-G

Variant summary

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

The NM_000208.4(INSR):​c.653-39200A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 151,994 control chromosomes in the GnomAD database, including 10,844 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 (10844 hom., cov: 31)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.342

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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSR	NM_000208.4	c.653-39200A>C		intron_variant		ENST00000302850.10
INSR	NM_001079817.3	c.653-39200A>C		intron_variant
INSR	XM_011527988.3	c.653-39200A>C		intron_variant
INSR	XM_011527989.4	c.653-39200A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSR	ENST00000302850.10	c.653-39200A>C		intron_variant		1	NM_000208.4	A2
INSR	ENST00000341500.9	c.653-39200A>C		intron_variant		1		P3
INSR	ENST00000598216.1	n.628-39200A>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55757 AN: 151876 Hom.: 10830 Cov.: 31

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.377

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

GnomAD4 genome AF: 0.367 AC: 55794 AN: 151994 Hom.: 10844 Cov.: 31 AF XY: 0.363 AC XY: 26974 AN XY: 74256

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.418

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.389

Gnomad4 SAS AF: 0.299

Gnomad4 FIN AF: 0.381

Gnomad4 NFE AF: 0.431

Gnomad4 OTH AF: 0.374

Alfa AF: 0.417 Hom.: 24052

Bravo AF: 0.366

Asia WGS AF: 0.288 AC: 1004 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.3
DANN	Benign	0.71

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: rs4804416; hg19: chr19-7223848;