6-18121516-G-T

Variant names:

• chr6-18121516-G-T
• rs78324544
• NM_198586.3:c.1091C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.06

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]

ACMG classification

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
NHLRC1	NM_198586.3	c.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
NHLRC1	ENST00000340650.6	c.1091C>A	p.Ser364*	stop_gained	Exon 1 of 1	6	NM_198586.3	ENSP00000345464.3

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

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

Other links and lift over

dbSNP: rs78324544; hg19: chr6-18121747;