rs139029314

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_198586.3(NHLRC1):c.32C>A(p.Ala11Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,596,788 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 7 hom. )

Consequence

NHLRC1
NM_198586.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 0.553

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 was made for transcript

Our verdict: Benign. The variant received -12 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=0.0068249106).

BP6

Variant 6-18122575-G-T is Benign according to our data. Variant chr6-18122575-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167350.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2, Benign=4}. Variant chr6-18122575-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00175 (267/152342) while in subpopulation AMR AF = 0.00307 (47/15306). AF 95% confidence interval is 0.00248. There are 0 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHLRC1	NM_198586.3 link	c.32C>A	p.Ala11Glu	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.32C>A	p.Ala11Glu	missense_variant	Exon 1 of 1	6	NM_198586.3	ENSP00000345464.3		Q6VVB1

Frequencies

GnomAD3 genomes

AF:

0.00175

AC:

267

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00307

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00140

AC:

311

AN:

221370

AF XY:

0.00129

show subpopulations

Gnomad AFR exome

AF:

0.000594

Gnomad AMR exome

AF:

0.00235

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000874

Gnomad NFE exome

AF:

0.00211

Gnomad OTH exome

AF:

0.00158

GnomAD4 exome

AF:

0.00231

AC:

3330

AN:

1444446

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1581

AN XY:

718970

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

AC:

AN:

33414

Gnomad4 AMR exome

AF:

0.00251

AC:

112

AN:

44674

Gnomad4 ASJ exome

AF:

0.000115

AC:

AN:

26078

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39668

Gnomad4 SAS exome

AF:

0.0000580

AC:

AN:

86188

Gnomad4 FIN exome

AF:

0.0000800

AC:

AN:

37522

Gnomad4 NFE exome

AF:

0.00275

AC:

3053

AN:

1111458

Gnomad4 Remaining exome

AF:

0.00239

AC:

144

AN:

60142

Heterozygous variant carriers

196

392

588

784

980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<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:

0.00175

AC:

267

AN:

152342

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

112

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000577

AC:

0.00057709

AN:

0.00057709

Gnomad4 AMR

AF:

0.00307

AC:

0.00307069

AN:

0.00307069

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000193

AC:

0.000193349

AN:

0.000193349

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00281

AC:

0.00280783

AN:

0.00280783

Gnomad4 OTH

AF:

0.00189

AC:

0.00189394

AN:

0.00189394

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.00201

Hom.:

Bravo

AF:

0.00189

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00101

AC:

ESP6500EA

AF:

0.00202

AC:

ExAC

AF:

0.00123

AC:

142

EpiCase

AF:

0.00278

EpiControl

AF:

0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 10, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 03, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NHLRC1: BS2 -

Dec 10, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 11, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lafora disease

Uncertain:1Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Nov 09, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 29, 2024

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. -

NHLRC1-related disorder

Benign:1

Oct 24, 2019

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

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.29

CADD

Benign

3.4

DANN

Benign

0.54

DEOGEN2

Benign

0.17

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.34

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.5

REVEL

Benign

0.26

Sift

Benign

1.0

Sift4G

Benign

0.54

Polyphen

0.0020

Vest4

0.085

MVP

0.64

MPC

0.47

ClinPred

0.0052

GERP RS

0.95

Varity_R

0.058

gMVP

0.50

Mutation Taster

=98/2

polymorphism

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