Variant rs28940575 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_198586.3(NHLRC1):c.76T>A(p.Cys26Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000626 in 1,597,434 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 Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

NHLRC1
NM_198586.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 7.99

Variant links:

Genes affected

NHLRC1 (HGNC:21576): (NHL repeat containing E3 ubiquitin protein ligase 1) The protein encoded by this gene is a single subunit E3 ubiquitin ligase. Laforin is polyubiquitinated by the encoded protein. Defects in this intronless gene lead to an accumulation of laforin and onset of Lafora disease, also known as progressive myoclonic epilepsy type 2 (EPM2).[provided by RefSeq, Mar 2010]

NHLRC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a zinc_finger_region RING-type (size 46) in uniprot entity NHLC1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_198586.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 6-18122531-A-T is Pathogenic according to our data. Variant chr6-18122531-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 2586.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHLRC1	NM_198586.3 link	c.76T>A	p.Cys26Ser	missense_variant	1/1	ENST00000340650.6	NP_940988.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHLRC1	ENST00000340650.6 link	c.76T>A	p.Cys26Ser	missense_variant	1/1	6	NM_198586.3	ENSP00000345464.3		Q6VVB1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000892

AC:

AN:

224274

Hom.:

AF XY:

0.0000161

AC XY:

AN XY:

124126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000198

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000623

AC:

AN:

1445236

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

719368

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Myoclonic epilepsy of Lafora 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2006

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 31, 2020

Published functional studies demonstrate a damaging effect (Gentry et al., 2005; Rao et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); A different missense change at this residue (C26Y) has been reported in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 18029386, 17908927, 18617530, 17337485, 19892702, 15930137, 16950819, 12958597) -

Lafora disease

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.68

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.5

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.91

Gain of disorder (P = 0.0207);

MVP

0.98

MPC

1.4

ClinPred

0.97

GERP RS

3.9

Varity_R

0.98

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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