rs10949483

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_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

Publications

38 publications found

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 Gene-Disease associations (from GenCC):

Lafora disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics

NHLRC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.49521 (below the threshold of 3.09). Trascript score misZ: -0.085446 (below the threshold of 3.09). GenCC associations: The gene is linked to Lafora disease.

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 VariationId is 129767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
NHLRC1	NM_198586.3 link	c.332C>T	p.Pro111Leu	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.332C>T	p.Pro111Leu	missense_variant	Exon 1 of 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

GnomAD2 exomes

AF:

0.403

AC:

89747

AN:

222478

AF XY:

0.396

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 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

African (AFR)

AF:

0.234

AC:

7829

AN:

33424

American (AMR)

AF:

0.519

AC:

22893

AN:

44122

Ashkenazi Jewish (ASJ)

AF:

0.375

AC:

9738

AN:

25990

East Asian (EAS)

AF:

0.381

AC:

15082

AN:

39600

South Asian (SAS)

AF:

0.336

AC:

28927

AN:

86082

European-Finnish (FIN)

AF:

0.428

AC:

18358

AN:

42864

Middle Eastern (MID)

AF:

0.374

AC:

2149

AN:

5750

European-Non Finnish (NFE)

AF:

0.396

AC:

439220

AN:

1110000

Other (OTH)

AF:

0.380

AC:

22880

AN:

60158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

24943

49887

74830

99774

124717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13710

27420

41130

54840

68550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.354

AC:

53911

AN:

152136

Hom.:

10019

Cov.:

AF XY:

0.356

AC XY:

26449

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.243

AC:

10110

AN:

41532

American (AMR)

AF:

0.422

AC:

6455

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.361

AC:

1251

AN:

3470

East Asian (EAS)

AF:

0.373

AC:

1917

AN:

5144

South Asian (SAS)

AF:

0.333

AC:

1604

AN:

4824

European-Finnish (FIN)

AF:

0.417

AC:

4428

AN:

10606

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.394

AC:

26797

AN:

67952

Other (OTH)

AF:

0.358

AC:

755

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1808

3616

5425

7233

9041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

532

1064

1596

2128

2660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.379

Hom.:

11148

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 27, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Lafora disease

Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 08, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

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

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.13

gMVP

0.46

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over