6-18122275-G-C

Variant names:

• chr6-18122275-G-C
• rs10949483
• NM_198586.3:c.332C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_198586.3(NHLRC1):​c.332C>G​(p.Pro111Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P111L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NHLRC1 NM_198586.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 38 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: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.49521 (below the threshold of 3.09). Trascript score misZ: -0.085446 (below the threshold of 3.09). GenCC associations: The gene is linked to Lafora disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2188392).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC1	NM_198586.3	MANE Select	c.332C>G	p.Pro111Arg	missense	Exon 1 of 1	NP_940988.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC1	ENST00000340650.6	TSL:6 MANE Select	c.332C>G	p.Pro111Arg	missense	Exon 1 of 1	ENSP00000345464.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.27
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.012	B
Vest4		0.12
MutPred		0.37		Loss of glycosylation at P111 (P = 0.025)
MVP		0.93
MPC		0.46
ClinPred		0.34	T
GERP RS		5.2
PromoterAI		0.010	Neutral
Varity_R		0.17
gMVP		0.46
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs10949483; hg19: chr6-18122506;