6-18121083-C-T

Position:

• chr6-18121083-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198586.3(NHLRC1):​c.*336G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 309,904 control chromosomes in the GnomAD database, including 639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (462 hom., cov: 32)
  • Exomes 𝑓: 0.038 (177 hom.)
• Consequence: NHLRC1 NM_198586.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.856

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 6-18121083-C-T is Benign according to our data. Variant chr6-18121083-C-T is described in ClinVar as [Benign]. Clinvar id is 356069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHLRC1	NM_198586.3	c.*336G>A		3_prime_UTR_variant	1/1	ENST00000340650.6	NP_940988.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHLRC1	ENST00000340650.6	c.*336G>A		3_prime_UTR_variant	1/1		NM_198586.3	ENSP00000345464	P1

Frequencies

GnomAD3 genomes AF: 0.0659 AC: 10018 AN: 151998 Hom.: 462 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0590

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.0295

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0424

Gnomad OTH AF: 0.0608

GnomAD4 exome AF: 0.0381 AC: 6011 AN: 157788 Hom.: 177 Cov.: 0 AF XY: 0.0354 AC XY: 2990 AN XY: 84400

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.0508

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0145

Gnomad4 SAS exome AF: 0.0157

Gnomad4 FIN exome AF: 0.0289

Gnomad4 NFE exome AF: 0.0416

Gnomad4 OTH exome AF: 0.0383

GnomAD4 genome AF: 0.0660 AC: 10033 AN: 152116 Hom.: 462 Cov.: 32 AF XY: 0.0638 AC XY: 4742 AN XY: 74374

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0589

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.0135

Gnomad4 SAS AF: 0.0184

Gnomad4 FIN AF: 0.0295

Gnomad4 NFE AF: 0.0424

Gnomad4 OTH AF: 0.0601

Alfa AF: 0.0447 Hom.: 316

Bravo AF: 0.0717

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lafora disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.1
DANN	Benign	0.73

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10949482; hg19: chr6-18121314;