Variant NM_000208.4:c.*104A>G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000208.4(INSR):c.*104A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.847 in 920,464 control chromosomes in the GnomAD database, including 331,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.84 ( 53240 hom., cov: 29)

Exomes 𝑓: 0.85 ( 278091 hom. )

Consequence

INSR
NM_000208.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.550

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 19-7116952-T-C is Benign according to our data. Variant chr19-7116952-T-C is described in ClinVar as [Benign]. Clinvar id is 330436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
INSR	NM_000208.4 link	c.*104A>G	3_prime_UTR_variant	Exon 22 of 22	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 link	c.*104A>G	3_prime_UTR_variant	Exon 21 of 21		NP_001073285.1	P06213-2
INSR	XM_011527988.3 link	c.*104A>G	3_prime_UTR_variant	Exon 22 of 22		XP_011526290.2
INSR	XM_011527989.4 link	c.*104A>G	3_prime_UTR_variant	Exon 21 of 21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INSR	ENST00000302850 link	c.*104A>G		3_prime_UTR_variant	Exon 22 of 22	1	NM_000208.4	ENSP00000303830.4		P06213-1
INSR	ENST00000341500 link	c.*104A>G		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000342838.4		P06213-2

Frequencies

GnomAD3 genomes

AF:

0.837

AC:

127054

AN:

151830

Hom.:

53192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.817

Gnomad AMI

AF:

0.820

Gnomad AMR

AF:

0.892

Gnomad ASJ

AF:

0.888

Gnomad EAS

AF:

0.954

Gnomad SAS

AF:

0.914

Gnomad FIN

AF:

0.772

Gnomad MID

AF:

0.886

Gnomad NFE

AF:

0.829

Gnomad OTH

AF:

0.855

GnomAD4 exome

AF:

0.849

AC:

652733

AN:

768516

Hom.:

278091

Cov.:

AF XY:

0.852

AC XY:

348143

AN XY:

408440

show subpopulations

Gnomad4 AFR exome

AF:

0.821

Gnomad4 AMR exome

AF:

0.925

Gnomad4 ASJ exome

AF:

0.890

Gnomad4 EAS exome

AF:

0.955

Gnomad4 SAS exome

AF:

0.910

Gnomad4 FIN exome

AF:

0.774

Gnomad4 NFE exome

AF:

0.833

Gnomad4 OTH exome

AF:

0.850

GnomAD4 genome

AF:

0.837

AC:

127159

AN:

151948

Hom.:

53240

Cov.:

AF XY:

0.838

AC XY:

62203

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.817

Gnomad4 AMR

AF:

0.892

Gnomad4 ASJ

AF:

0.888

Gnomad4 EAS

AF:

0.954

Gnomad4 SAS

AF:

0.914

Gnomad4 FIN

AF:

0.772

Gnomad4 NFE

AF:

0.829

Gnomad4 OTH

AF:

0.858

Alfa

AF:

0.839

Hom.:

59229

Bravo

AF:

0.845

Asia WGS

AF:

0.935

AC:

3250

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23315997, 20971123, 18192692) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Insulin-resistant diabetes mellitus AND acanthosis nigricans

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Rabson-Mendenhall syndrome

Benign:1

Jan 15, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leprechaunism syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.8

DANN

Benign

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over