6-18120937-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_198586.3(NHLRC1):c.*482C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 184,758 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (61 hom., cov: 33)
  • Exomes 𝑓: 0.024 (12 hom.)
• Consequence: NHLRC1 NM_198586.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.879

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 6-18120937-G-C is Benign according to our data. Variant chr6-18120937-G-C is described in ClinVar as [Benign]. Clinvar id is 356064.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0208 (3163/152286) while in subpopulation AMR AF= 0.043 (658/15292). AF 95% confidence interval is 0.0403. There are 61 homozygotes in gnomad4. There are 1481 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 61 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHLRC1	NM_198586.3	c.*482C>G		3_prime_UTR_variant	1/1	ENST00000340650.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHLRC1	ENST00000340650.6	c.*482C>G		3_prime_UTR_variant	1/1		NM_198586.3	P1

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3162 AN: 152168 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.00497

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00616

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.00753

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0279

Gnomad OTH AF: 0.0335

GnomAD4 exome AF: 0.0240 AC: 780 AN: 32472 Hom.: 12 Cov.: 0 AF XY: 0.0226 AC XY: 386 AN XY: 17066

Gnomad4 AFR exome AF: 0.00350

Gnomad4 AMR exome AF: 0.0528

Gnomad4 ASJ exome AF: 0.0199

Gnomad4 EAS exome AF: 0.0136

Gnomad4 SAS exome AF: 0.0189

Gnomad4 FIN exome AF: 0.0113

Gnomad4 NFE exome AF: 0.0227

Gnomad4 OTH exome AF: 0.0241

GnomAD4 genome AF: 0.0208 AC: 3163 AN: 152286 Hom.: 61 Cov.: 33 AF XY: 0.0199 AC XY: 1481 AN XY: 74474

Gnomad4 AFR AF: 0.00496

Gnomad4 AMR AF: 0.0430

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00598

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.00753

Gnomad4 NFE AF: 0.0279

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.00574 Hom.: 1

Bravo AF: 0.0237

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.20
Dann	Benign	0.27

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs114713758; hg19: chr6-18121168;