chr6-18122185-A-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBS1_Supporting

The NM_198586.3(NHLRC1):c.422T>C(p.Val141Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000228 in 1,613,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

NHLRC1
NM_198586.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 5.42

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 Likely_benign. Variant got -1 ACMG points.

PM1

In a repeat NHL 1 (size 44) in uniprot entity NHLC1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_198586.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.011676341).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00123 (187/152190) while in subpopulation AFR AF= 0.00431 (179/41534). AF 95% confidence interval is 0.00379. There are 0 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. Median coverage is 32. 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 rank	MANE	Protein	UniProt
NHLRC1	NM_198586.3 link	c.422T>C	p.Val141Ala	missense_variant	Exon 1 of 1	ENST00000340650.6	NP_940988.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHLRC1	ENST00000340650.6 link	c.422T>C	p.Val141Ala	missense_variant	Exon 1 of 1	6	NM_198586.3	ENSP00000345464.3		Q6VVB1

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

187

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00432

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00143

GnomAD3 exomes

AF:

0.000317

AC:

AN:

246324

Hom.:

AF XY:

0.000239

AC XY:

AN XY:

134096

show subpopulations

Gnomad AFR exome

AF:

0.00455

Gnomad AMR exome

AF:

0.000174

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:

0.00000903

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

181

AN:

1460816

Hom.:

Cov.:

AF XY:

0.0000991

AC XY:

AN XY:

726760

show subpopulations

Gnomad4 AFR exome

AF:

0.00457

Gnomad4 AMR exome

AF:

0.000224

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:

0.00000180

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.00123

AC:

187

AN:

152190

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00431

Gnomad4 AMR

AF:

0.000327

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:

0.00142

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.00143

ESP6500AA

AF:

0.00319

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000387

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jan 22, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jun 25, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Dec 18, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V141A variant (also known as c.422T>C), located in coding exon 1 of the NHLRC1 gene, results from a T to C substitution at nucleotide position 422. The valine at codon 141 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lafora disease

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NHLRC1-related disorder

Benign:1

May 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.45

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.51

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.012

MetaSVM

Uncertain

-0.24

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.40

Sift

Benign

0.083

Sift4G

Benign

0.24

Polyphen

0.013

Vest4

0.37

MVP

0.89

MPC

0.51

ClinPred

0.027

GERP RS

5.2

Varity_R

0.13

gMVP

0.77

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