6-18120798-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198586.3(NHLRC1):c.*621T>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 0.0814 in 153,632 control chromosomes in the GnomAD database, including 852 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.082 (851 hom., cov: 33)
  • Exomes 𝑓: 0.027 (1 hom.)
• Consequence: NHLRC1 NM_198586.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.300

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=-0.92).
• BP6: Variant 6-18120798-A-T is Benign according to our data. Variant chr6-18120798-A-T is described in ClinVar as [Benign]. Clinvar id is 356063.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHLRC1	NM_198586.3	c.*621T>A		3_prime_UTR_variant	1/1	ENST00000340650.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHLRC1	ENST00000340650.6	c.*621T>A		3_prime_UTR_variant	1/1		NM_198586.3	P1

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12453 AN: 152172 Hom.: 849 Cov.: 33

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.0427

Gnomad OTH AF: 0.0704

GnomAD4 exome AF: 0.0268 AC: 36 AN: 1342 Hom.: 1 Cov.: 0 AF XY: 0.0249 AC XY: 17 AN XY: 684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0242

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0295

Gnomad4 OTH exome AF: 0.0500

GnomAD4 genome AF: 0.0819 AC: 12475 AN: 152290 Hom.: 851 Cov.: 33 AF XY: 0.0794 AC XY: 5916 AN XY: 74470

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.0648

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.0135

Gnomad4 SAS AF: 0.0184

Gnomad4 FIN AF: 0.0297

Gnomad4 NFE AF: 0.0427

Gnomad4 OTH AF: 0.0697

Alfa AF: 0.0475 Hom.: 153

Bravo AF: 0.0901

Asia WGS AF: 0.0270 AC: 96 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 13, 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	-0.92
Cadd	Benign	2.2
Dann	Benign	0.49

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10949481; hg19: chr6-18121029;