rs752045674

Positions:

• chr6-18122504-G-A
• chr6-18122504-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_198586.3(NHLRC1):​c.103C>T​(p.His35Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: NHLRC1 NM_198586.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.869

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a zinc_finger_region RING-type (size 46) in uniprot entity NHLC1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_198586.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3292954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHLRC1	NM_198586.3	c.103C>T	p.His35Tyr	missense_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.103C>T	p.His35Tyr	missense_variant	1/1		NM_198586.3	ENSP00000345464	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.031
Eigen_PC	Benign	0.099
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.22	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.27
Sift	Benign	0.18	T
Sift4G	Benign	0.37	T
Polyphen		0.78	P
Vest4		0.20
MutPred		0.56		Gain of solvent accessibility (P = 0.0018);
MVP		0.89
MPC		0.82
ClinPred		0.37	T
GERP RS		4.1
Varity_R		0.20
gMVP		0.37

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: rs752045674; hg19: chr6-18122735;