rs7254060

Variant names:

• chr19-7283403-A-G
• rs7254060
• NM_000208.4:c.100+10389T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-7283403-A-G
• chr19-7283403-A-T

Variant summary

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

The NM_000208.4(INSR):​c.100+10389T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 151,936 control chromosomes in the GnomAD database, including 49,436 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 0.78 (49436 hom., cov: 30)
• Consequence: INSR NM_000208.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.283
• Publications: 10 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4	c.100+10389T>C		intron_variant	Intron 1 of 21	ENST00000302850.10	NP_000199.2
INSR	NM_001079817.3	c.100+10389T>C		intron_variant	Intron 1 of 20		NP_001073285.1
INSR	XM_011527988.3	c.100+10389T>C		intron_variant	Intron 1 of 21		XP_011526290.2
INSR	XM_011527989.4	c.100+10389T>C		intron_variant	Intron 1 of 20		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850.10	c.100+10389T>C		intron_variant	Intron 1 of 21	1	NM_000208.4	ENSP00000303830.4
INSR	ENST00000341500.9	c.100+10389T>C		intron_variant	Intron 1 of 20	1		ENSP00000342838.4
INSR	ENST00000598216.1	n.75+10389T>C		intron_variant	Intron 1 of 9	1

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118501 AN: 151818 Hom.: 49431 Cov.: 30

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.991

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.954

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.798

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.941

Gnomad OTH AF: 0.819

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

GnomAD4 genome AF: 0.780 AC: 118533 AN: 151936 Hom.: 49436 Cov.: 30 AF XY: 0.776 AC XY: 57614 AN XY: 74260

African (AFR) AF: 0.463 AC: 19165 AN: 41380

American (AMR) AF: 0.800 AC: 12187 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.954 AC: 3310 AN: 3470

East Asian (EAS) AF: 0.781 AC: 4019 AN: 5146

South Asian (SAS) AF: 0.799 AC: 3853 AN: 4820

European-Finnish (FIN) AF: 0.865 AC: 9132 AN: 10556

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.941 AC: 63974 AN: 68006

Other (OTH) AF: 0.817 AC: 1726 AN: 2112

Alfa AF: 0.886 Hom.: 193125

Bravo AF: 0.762

Asia WGS AF: 0.773 AC: 2689 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.6
DANN	Benign	0.70
PhyloP100		0.28
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: rs7254060; hg19: chr19-7283414;