6-18122295-A-G

Position:

• chr6-18122295-A-G

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.312T>C​(p.His104His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0956 in 1,593,860 control chromosomes in the GnomAD database, including 8,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1232 hom., cov: 33)
  • Exomes 𝑓: 0.094 (6823 hom.)
• Consequence: NHLRC1 NM_198586.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.631

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=-0.92).
• BP6: Variant 6-18122295-A-G is Benign according to our data. Variant chr6-18122295-A-G is described in ClinVar as [Benign]. Clinvar id is 129766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-18122295-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHLRC1	NM_198586.3	c.312T>C	p.His104His	synonymous_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.312T>C	p.His104His	synonymous_variant	1/1	6	NM_198586.3	ENSP00000345464.3

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17446 AN: 152110 Hom.: 1230 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.0628

Gnomad AMR AF: 0.0983

Gnomad ASJ AF: 0.0775

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.0816

Gnomad FIN AF: 0.0607

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0906

Gnomad OTH AF: 0.117

GnomAD3 exomes AF: 0.0861 AC: 18216 AN: 211654 Hom.: 923 AF XY: 0.0843 AC XY: 9899 AN XY: 117380

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.0820

Gnomad ASJ exome AF: 0.0738

Gnomad EAS exome AF: 0.0143

Gnomad SAS exome AF: 0.0807

Gnomad FIN exome AF: 0.0721

Gnomad NFE exome AF: 0.0895

Gnomad OTH exome AF: 0.0906

GnomAD4 exome AF: 0.0936 AC: 134892 AN: 1441632 Hom.: 6823 Cov.: 36 AF XY: 0.0923 AC XY: 66167 AN XY: 716930

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.0840

Gnomad4 ASJ exome AF: 0.0773

Gnomad4 EAS exome AF: 0.0131

Gnomad4 SAS exome AF: 0.0791

Gnomad4 FIN exome AF: 0.0742

Gnomad4 NFE exome AF: 0.0959

Gnomad4 OTH exome AF: 0.0913

GnomAD4 genome AF: 0.115 AC: 17460 AN: 152228 Hom.: 1232 Cov.: 33 AF XY: 0.111 AC XY: 8300 AN XY: 74444

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.0981

Gnomad4 ASJ AF: 0.0775

Gnomad4 EAS AF: 0.0142

Gnomad4 SAS AF: 0.0810

Gnomad4 FIN AF: 0.0607

Gnomad4 NFE AF: 0.0906

Gnomad4 OTH AF: 0.115

Alfa AF: 0.0850 Hom.: 533

Bravo AF: 0.121

Asia WGS AF: 0.0660 AC: 230 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 18, 2016	- -

Lafora disease Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.6
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs115931931; hg19: chr6-18122526; COSMIC: COSV61481531;