rs10949483

chr6-18122275-G-Achr6-18122275-G-Cchr6-18122275-G-T

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.332C>T(p.Pro111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,600,126 control chromosomes in the GnomAD database, including 122,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10019 hom., cov: 33)
  • Exomes 𝑓: 0.39 (112505 hom.)
• Consequence: NHLRC1 NM_198586.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.58

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 (MetaRNN=0.0011947155).
• BP6: Variant 6-18122275-G-A is Benign according to our data. Variant chr6-18122275-G-A is described in ClinVar as [Benign]. Clinvar id is 129767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-18122275-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHLRC1	NM_198586.3	c.332C>T	p.Pro111Leu	missense_variant	1/1	ENST00000340650.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHLRC1	ENST00000340650.6	c.332C>T	p.Pro111Leu	missense_variant	1/1		NM_198586.3	P1

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53893 AN: 152020 Hom.: 10017 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.358

GnomAD3 exomes AF: 0.403 AC: 89747 AN: 222478 Hom.: 18505 AF XY: 0.396 AC XY: 48758 AN XY: 123012

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.533

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.393

Gnomad SAS exome AF: 0.340

Gnomad FIN exome AF: 0.436

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.392 AC: 567076 AN: 1447990 Hom.: 112505 Cov.: 56 AF XY: 0.390 AC XY: 281056 AN XY: 720376

Gnomad4 AFR exome AF: 0.234

Gnomad4 AMR exome AF: 0.519

Gnomad4 ASJ exome AF: 0.375

Gnomad4 EAS exome AF: 0.381

Gnomad4 SAS exome AF: 0.336

Gnomad4 FIN exome AF: 0.428

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.380

GnomAD4 genome AF: 0.354 AC: 53911 AN: 152136 Hom.: 10019 Cov.: 33 AF XY: 0.356 AC XY: 26449 AN XY: 74382

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.422

Gnomad4 ASJ AF: 0.361

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.417

Gnomad4 NFE AF: 0.394

Gnomad4 OTH AF: 0.358

Alfa AF: 0.384 Hom.: 9228

Bravo AF: 0.353

TwinsUK AF: 0.399 AC: 1481

ALSPAC AF: 0.410 AC: 1579

ESP6500AA AF: 0.243 AC: 1051

ESP6500EA AF: 0.385 AC: 3258

ExAC AF: 0.386 AC: 45836

Asia WGS AF: 0.359 AC: 1245 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lafora disease Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 27, 2013	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 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. -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0012	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.93	P
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.33
Sift	Benign	0.032	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.16	B
Vest4		0.067
MPC		0.70
ClinPred		0.034	T
GERP RS		5.2
Varity_R		0.13
gMVP		0.46

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: rs10949483; hg19: chr6-18122506; COSMIC: COSV61481325;