19-7200979-C-T

Variant names:

• chr19-7200979-C-T
• rs4499341
• NM_000208.4:c.653-16342G>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.653-16342G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 151,768 control chromosomes in the GnomAD database, including 25,130 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 0.56 (25130 hom., cov: 30)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Donohue syndrome

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

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

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

ENSG00000303888 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	NM_000208.4	MANE Select	c.653-16342G>A		intron	N/A	NP_000199.2	P06213-1
	INSR	NM_001079817.3		c.653-16342G>A		intron	N/A	NP_001073285.1	P06213-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INSR	ENST00000302850.10	TSL:1 MANE Select	c.653-16342G>A		intron	N/A	ENSP00000303830.4	P06213-1
	INSR	ENST00000341500.9	TSL:1	c.653-16342G>A		intron	N/A	ENSP00000342838.4	P06213-2
	INSR	ENST00000598216.1	TSL:1	n.628-16342G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85375 AN: 151652 Hom.: 25121 Cov.: 30

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.631

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.741

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.568

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

GnomAD4 genome AF: 0.563 AC: 85402 AN: 151768 Hom.: 25130 Cov.: 30 AF XY: 0.567 AC XY: 42047 AN XY: 74146

African (AFR) AF: 0.367 AC: 15162 AN: 41312

American (AMR) AF: 0.631 AC: 9623 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 2282 AN: 3462

East Asian (EAS) AF: 0.610 AC: 3154 AN: 5172

South Asian (SAS) AF: 0.508 AC: 2440 AN: 4804

European-Finnish (FIN) AF: 0.741 AC: 7792 AN: 10520

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.633 AC: 43030 AN: 67956

Other (OTH) AF: 0.567 AC: 1188 AN: 2096

Alfa AF: 0.604 Hom.: 14427

Bravo AF: 0.550

Asia WGS AF: 0.539 AC: 1876 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.10
DANN	Benign	0.68
PhyloP100		-1.5
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: rs4499341; hg19: chr19-7200990;