6-18122275-G-A

Position:

chr6-18122275-G-A

Variant summary

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

The NM_198586.3(NHLRC1):c.332C>T(p.Pro111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,600,126 control chromosomes in the GnomAD database, including 122,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10019 hom., cov: 33)

Exomes 𝑓: 0.39 ( 112505 hom. )

Consequence

NHLRC1
NM_198586.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.58

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011947155).

BP6

Variant 6-18122275-G-A is Benign according to our data. Variant chr6-18122275-G-A is described in ClinVar as [Benign]. Clinvar id is 129767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-18122275-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHLRC1	NM_198586.3 linkuse as main transcript	c.332C>T	p.Pro111Leu	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 linkuse as main transcript	c.332C>T	p.Pro111Leu	missense_variant	1/1	6	NM_198586.3	ENSP00000345464.3		Q6VVB1

Frequencies

GnomAD3 genomes

AF:

0.355

AC:

53893

AN:

152020

Hom.:

10017

Cov.:

show subpopulations

Gnomad AFR

AF:

0.244

Gnomad AMI

AF:

0.550

Gnomad AMR

AF:

0.422

Gnomad ASJ

AF:

0.361

Gnomad EAS

AF:

0.373

Gnomad SAS

AF:

0.331

Gnomad FIN

AF:

0.417

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.394

Gnomad OTH

AF:

0.358

GnomAD3 exomes

AF:

0.403

AC:

89747

AN:

222478

Hom.:

18505

AF XY:

0.396

AC XY:

48758

AN XY:

123012

show subpopulations

Gnomad AFR exome

AF:

0.244

Gnomad AMR exome

AF:

0.533

Gnomad ASJ exome

AF:

0.373

Gnomad EAS exome

AF:

0.393

Gnomad SAS exome

AF:

0.340

Gnomad FIN exome

AF:

0.436

Gnomad NFE exome

AF:

0.400

Gnomad OTH exome

AF:

0.406

GnomAD4 exome

AF:

0.392

AC:

567076

AN:

1447990

Hom.:

112505

Cov.:

AF XY:

0.390

AC XY:

281056

AN XY:

720376

show subpopulations

Gnomad4 AFR exome

AF:

0.234

Gnomad4 AMR exome

AF:

0.519

Gnomad4 ASJ exome

AF:

0.375

Gnomad4 EAS exome

AF:

0.381

Gnomad4 SAS exome

AF:

0.336

Gnomad4 FIN exome

AF:

0.428

Gnomad4 NFE exome

AF:

0.396

Gnomad4 OTH exome

AF:

0.380

GnomAD4 genome

AF:

0.354

AC:

53911

AN:

152136

Hom.:

10019

Cov.:

AF XY:

0.356

AC XY:

26449

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.243

Gnomad4 AMR

AF:

0.422

Gnomad4 ASJ

AF:

0.361

Gnomad4 EAS

AF:

0.373

Gnomad4 SAS

AF:

0.333

Gnomad4 FIN

AF:

0.417

Gnomad4 NFE

AF:

0.394

Gnomad4 OTH

AF:

0.358

Alfa

AF:

0.384

Hom.:

9228

Bravo

AF:

0.353

TwinsUK

AF:

0.399

AC:

1481

ALSPAC

AF:

0.410

AC:

1579

ESP6500AA

AF:

0.243

AC:

1051

ESP6500EA

AF:

0.385

AC:

3258

ExAC

AF:

0.386

AC:

45836

Asia WGS

AF:

0.359

AC:

1245

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 71% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 66. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Lafora disease

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0012

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.33

Sift

Benign

0.032

Sift4G

Uncertain

0.0080

Polyphen

0.16

Vest4

0.067

MPC

0.70

ClinPred

0.034

GERP RS

5.2

Varity_R

0.13

gMVP

0.46

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