rs4804433

Positions:

• chr19-7240765-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.652+26580C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 152,014 control chromosomes in the GnomAD database, including 39,201 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 0.71 (39201 hom., cov: 32)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07

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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4	c.652+26580C>A		intron_variant		ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.652+26580C>A		intron_variant			NP_001073285.1
INSR	XM_011527988.3	c.652+26580C>A		intron_variant			XP_011526290.2
INSR	XM_011527989.4	c.652+26580C>A		intron_variant			XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.652+26580C>A		intron_variant		1	NM_000208.4	ENSP00000303830	A2
INSR	ENST00000341500.9	c.652+26580C>A		intron_variant		1		ENSP00000342838	P3
INSR	ENST00000598216.1	n.627+26580C>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107876 AN: 151896 Hom.: 39170 Cov.: 32

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.803

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.774

Gnomad OTH AF: 0.736

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

GnomAD4 genome AF: 0.710 AC: 107963 AN: 152014 Hom.: 39201 Cov.: 32 AF XY: 0.706 AC XY: 52447 AN XY: 74298

Gnomad4 AFR AF: 0.666

Gnomad4 AMR AF: 0.668

Gnomad4 ASJ AF: 0.803

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.736

Gnomad4 FIN AF: 0.709

Gnomad4 NFE AF: 0.774

Gnomad4 OTH AF: 0.739

Alfa AF: 0.751 Hom.: 6594

Bravo AF: 0.703

Asia WGS AF: 0.560 AC: 1949 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.42
DANN	Benign	0.61

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: rs4804433; hg19: chr19-7240776;