19-7170230-C-T

Variant names:

• chr19-7170230-C-T
• rs7251963
• NM_000208.4:c.1483+307G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000208.4(INSR):​c.1483+307G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 151,226 control chromosomes in the GnomAD database, including 21,944 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 0.52 (21944 hom., cov: 28)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.921
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• insulin-resistance syndrome type A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• Donohue syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• hyperinsulinism due to INSR deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics
• Rabson-Mendenhall syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.1483+307G>A		intron_variant	Intron 6 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.1483+307G>A		intron_variant	Intron 6 of 20		NP_001073285.1
INSR	XM_011527988.3	c.1483+307G>A		intron_variant	Intron 6 of 21		XP_011526290.2
INSR	XM_011527989.4	c.1483+307G>A		intron_variant	Intron 6 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.1483+307G>A		intron_variant	Intron 6 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.1483+307G>A		intron_variant	Intron 6 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.1458+307G>A		intron_variant	Intron 6 of 9	1

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78428 AN: 151108 Hom.: 21882 Cov.: 28

Gnomad AFR AF: 0.740

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.538

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

GnomAD4 genome AF: 0.519 AC: 78534 AN: 151226 Hom.: 21944 Cov.: 28 AF XY: 0.519 AC XY: 38323 AN XY: 73816

African (AFR) AF: 0.740 AC: 30461 AN: 41148

American (AMR) AF: 0.427 AC: 6458 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 1879 AN: 3468

East Asian (EAS) AF: 0.316 AC: 1614 AN: 5112

South Asian (SAS) AF: 0.554 AC: 2654 AN: 4792

European-Finnish (FIN) AF: 0.452 AC: 4728 AN: 10468

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28902 AN: 67810

Other (OTH) AF: 0.543 AC: 1135 AN: 2092

Alfa AF: 0.454 Hom.: 62464

Bravo AF: 0.524

Asia WGS AF: 0.519 AC: 1805 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.27
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7251963; hg19: chr19-7170241;