chr6-18121083-C-T

Variant names:

• chr6-18121083-C-T
• rs10949482
• NM_198586.3:c.*336G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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 -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 VariationId 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.

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.*336G>A		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.*336G>A		3_prime_UTR	Exon 1 of 1	ENSP00000345464.3	Q6VVB1

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

African (AFR) AF: 0.142 AC: 703 AN: 4936

American (AMR) AF: 0.0508 AC: 304 AN: 5988

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 51 AN: 4382

East Asian (EAS) AF: 0.0145 AC: 105 AN: 7258

South Asian (SAS) AF: 0.0157 AC: 397 AN: 25222

European-Finnish (FIN) AF: 0.0289 AC: 194 AN: 6718

Middle Eastern (MID) AF: 0.0148 AC: 9 AN: 608

European-Non Finnish (NFE) AF: 0.0416 AC: 3935 AN: 94504

Other (OTH) AF: 0.0383 AC: 313 AN: 8172

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

African (AFR) AF: 0.134 AC: 5560 AN: 41466

American (AMR) AF: 0.0589 AC: 900 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 64 AN: 3468

East Asian (EAS) AF: 0.0135 AC: 70 AN: 5170

South Asian (SAS) AF: 0.0184 AC: 89 AN: 4828

European-Finnish (FIN) AF: 0.0295 AC: 313 AN: 10596

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0424 AC: 2885 AN: 67992

Other (OTH) AF: 0.0601 AC: 127 AN: 2112

Alfa AF: 0.0493 Hom.: 586

Bravo AF: 0.0717

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Lafora disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.1
DANN	Benign	0.73
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10949482; hg19: chr6-18121314;