NM_198586.3:c.*482C>G

Variant names:

• chr6-18120937-G-C
• rs114713758
• NM_198586.3:c.*482C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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]

NHLRC1 Gene-Disease associations (from GenCC):

• Lafora disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198586.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC1	NM_198586.3	MANE Select	c.*482C>G		3_prime_UTR	Exon 1 of 1	NP_940988.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC1	ENST00000340650.6	TSL:6 MANE Select	c.*482C>G		3_prime_UTR	Exon 1 of 1	ENSP00000345464.3	Q6VVB1

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

African (AFR) AF: 0.00350 AC: 2 AN: 572

American (AMR) AF: 0.0528 AC: 173 AN: 3274

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 10 AN: 502

East Asian (EAS) AF: 0.0136 AC: 27 AN: 1990

South Asian (SAS) AF: 0.0189 AC: 78 AN: 4118

European-Finnish (FIN) AF: 0.0113 AC: 11 AN: 970

Middle Eastern (MID) AF: 0.0104 AC: 1 AN: 96

European-Non Finnish (NFE) AF: 0.0227 AC: 439 AN: 19332

Other (OTH) AF: 0.0241 AC: 39 AN: 1618

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

African (AFR) AF: 0.00496 AC: 206 AN: 41548

American (AMR) AF: 0.0430 AC: 658 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3468

East Asian (EAS) AF: 0.00598 AC: 31 AN: 5186

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4830

European-Finnish (FIN) AF: 0.00753 AC: 80 AN: 10624

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0279 AC: 1897 AN: 68018

Other (OTH) AF: 0.0331 AC: 70 AN: 2114

Alfa AF: 0.00574 Hom.: 1

Bravo AF: 0.0237

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Lafora disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.20
DANN	Benign	0.27
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs114713758; hg19: chr6-18121168;