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. 15/22 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:2B:10

Conservation

PhyloP100: 0.553

Publications

5 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:

ENSG00000307971 (HGNC:):

ENSG00000307971 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 VariationId is 167350.

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 passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198586.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC1	NM_198586.3	MANE Select	c.32C>A	p.Ala11Glu	missense	Exon 1 of 1	NP_940988.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC1	ENST00000340650.6	TSL:6 MANE Select	c.32C>A	p.Ala11Glu	missense	Exon 1 of 1	ENSP00000345464.3
	ENSG00000307971	ENST00000830126.1		n.-191G>T		upstream_gene	N/A

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

African (AFR)

AF:

0.000239

AC:

AN:

33414

American (AMR)

AF:

0.00251

AC:

112

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.0000800

AC:

AN:

37522

Middle Eastern (MID)

AF:

0.000377

AC:

AN:

5302

European-Non Finnish (NFE)

AF:

0.00275

AC:

3053

AN:

1111458

Other (OTH)

AF:

0.00239

AC:

144

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

196

392

588

784

980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.000577

AC:

AN:

41588

American (AMR)

AF:

0.00307

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00281

AC:

191

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Lafora disease (2)

Inborn genetic diseases (1)

Myoclonic epilepsy of Lafora 1 (1)

NHLRC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.29

CADD

Benign

3.4

(source)

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

PhyloP100

0.55

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

PromoterAI

0.075

Neutral

(source)

Varity_R

0.058

gMVP

0.50

Mutation Taster

=98/2

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over