rs367649330
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_198586.3(NHLRC1):āc.584A>Gā(p.Asp195Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Consequence
NHLRC1
NM_198586.3 missense
NM_198586.3 missense
Scores
2
14
3
Clinical Significance
Conservation
PhyloP100: 5.57
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_198586.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.915
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NHLRC1 | NM_198586.3 | c.584A>G | p.Asp195Gly | missense_variant | 1/1 | ENST00000340650.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NHLRC1 | ENST00000340650.6 | c.584A>G | p.Asp195Gly | missense_variant | 1/1 | NM_198586.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251428Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135904
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GnomAD4 exome Cov.: 31
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74320
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ESP6500AA
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Lafora disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 578187). This variant has not been reported in the literature in individuals affected with NHLRC1-related conditions. This variant is present in population databases (rs367649330, gnomAD 0.007%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 195 of the NHLRC1 protein (p.Asp195Gly). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at