rs755298967

Positions:

chr19-7293808-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting

The NM_000208.4(INSR):c.84C>A(p.His28Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,355,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

INSR
NM_000208.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.447

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:

INSR (HGNC:):

INSR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), INSR. . Gene score misZ 3.8314 (greater than the threshold 3.09). Trascript score misZ 5.4593 (greater than threshold 3.09). GenCC has associacion of gene with insulin-resistance syndrome type A, hyperinsulinism due to INSR deficiency, Rabson-Mendenhall syndrome, Donohue syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.18188745).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000066 (10/151492) while in subpopulation AFR AF= 0.000242 (10/41334). AF 95% confidence interval is 0.000131. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INSR	NM_000208.4 linkuse as main transcript	c.84C>A	p.His28Gln	missense_variant	1/22	ENST00000302850.10	NP_000199.2	P06213-1
INSR	NM_001079817.3 linkuse as main transcript	c.84C>A	p.His28Gln	missense_variant	1/21		NP_001073285.1	P06213-2
INSR	XM_011527988.3 linkuse as main transcript	c.84C>A	p.His28Gln	missense_variant	1/22		XP_011526290.2
INSR	XM_011527989.4 linkuse as main transcript	c.84C>A	p.His28Gln	missense_variant	1/21		XP_011526291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
INSR	ENST00000302850.10 linkuse as main transcript	c.84C>A	p.His28Gln	missense_variant	1/22	1	NM_000208.4	ENSP00000303830.4	P06213-1
INSR	ENST00000341500.9 linkuse as main transcript	c.84C>A	p.His28Gln	missense_variant	1/21	1		ENSP00000342838.4	P06213-2
INSR	ENST00000598216.1 linkuse as main transcript	n.59C>A		non_coding_transcript_exon_variant	1/10	1

Frequencies

GnomAD3 genomes

AF:

0.0000660

AC:

AN:

151492

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000498

AC:

AN:

1204468

Hom.:

Cov.:

AF XY:

0.00000509

AC XY:

AN XY:

589216

show subpopulations

Gnomad4 AFR exome

AF:

0.000198

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000207

GnomAD4 genome

AF:

0.0000660

AC:

AN:

151492

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

73962

show subpopulations

Gnomad4 AFR

AF:

0.000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000307

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 22, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.40

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.41

T;T

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.32

N;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.46

N;N

REVEL

Benign

0.10

Sift

Benign

0.25

T;T

Sift4G

Benign

0.63

T;T

Polyphen

0.038

B;P

Vest4

0.15

MutPred

0.32

Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);

MVP

0.59

MPC

0.76

ClinPred

0.083

GERP RS

-0.77

Varity_R

0.23

gMVP

0.37

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