Variant rs397515521 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_000207.3(INS):c.3G>T(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000685 in 1,459,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

INS
NM_000207.3 start_lost

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 5.42

Variant links:

Genes affected

INS (HGNC:6081): (insulin) This gene encodes insulin, a peptide hormone that plays a vital role in the regulation of carbohydrate and lipid metabolism. After removal of the precursor signal peptide, proinsulin is post-translationally cleaved into three peptides: the B chain and A chain peptides, which are covalently linked via two disulfide bonds to form insulin, and C-peptide. Binding of insulin to the insulin receptor (INSR) stimulates glucose uptake. A multitude of mutant alleles with phenotypic effects have been identified, including insulin-dependent diabetes mellitus, permanent neonatal diabetes diabetes mellitus, maturity-onset diabetes of the young type 10 and hyperproinsulinemia. There is a read-through gene, INS-IGF2, which overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region. [provided by RefSeq, May 2020]

INS links:

INS-IGF2 (HGNC:):

INS-IGF2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_000207.3 (INS) was described as [Likely_pathogenic] in ClinVar as 1455986

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS	NM_000207.3 linkuse as main transcript	c.3G>T	p.Met1?	start_lost	2/3	ENST00000381330.5
INS-IGF2	NR_003512.4 linkuse as main transcript	n.62G>T		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000381330.5 linkuse as main transcript	c.3G>T	p.Met1?	start_lost	2/3	1	NM_000207.3	P1	P01308-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459906

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726274

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

Permanent neonatal diabetes mellitus

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.60

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;D;D;D;.;.

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

D;.;.;D;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Uncertain

0.71

MutationTaster

Benign

1.0

D;N;N;N;N;N

PROVEAN

Uncertain

-2.4

N;N;N;N;N;N

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;.;D

Polyphen

0.99

D;D;D;D;.;D

Vest4

0.83

MutPred

0.97

Loss of disorder (P = 0.0147);Loss of disorder (P = 0.0147);Loss of disorder (P = 0.0147);Loss of disorder (P = 0.0147);Loss of disorder (P = 0.0147);Loss of disorder (P = 0.0147);

MVP

0.84

ClinPred

0.99

GERP RS

3.0

Varity_R

0.96

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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