6-18121516-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_198586.3(NHLRC1):​c.1091C>A​(p.Ser364*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

NHLRC1
NM_198586.3 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.06
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0816 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-18121516-G-T is Pathogenic according to our data. Variant chr6-18121516-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 860910.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NHLRC1NM_198586.3 linkc.1091C>A p.Ser364* stop_gained Exon 1 of 1 ENST00000340650.6 NP_940988.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NHLRC1ENST00000340650.6 linkc.1091C>A p.Ser364* stop_gained Exon 1 of 1 6 NM_198586.3 ENSP00000345464.3 Q6VVB1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Lafora disease Pathogenic:1
Dec 27, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the NHLRC1 protein. Other variant(s) that disrupt this region (Val367Trpfs*21) have been determined to be pathogenic (PMID: 12958597). This variant is also known as p.V367fs20 in the literature. This suggests that variants that disrupt this region of the protein are likely to be causative of disease. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with progressive myoclonic epilepsy (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the NHLRC1 gene (p.Ser364*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acids of the NHLRC1 protein. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
34
DANN
Uncertain
0.98
Eigen
Benign
0.15
Eigen_PC
Benign
-0.095
FATHMM_MKL
Benign
0.67
D
Vest4
0.69
GERP RS
4.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs78324544; hg19: chr6-18121747; API