rs118204025
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The ENST00000225927.7(NAGLU):āc.942C>Gā(p.Phe314Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,792 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 Pathogenic (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F314S) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000225927.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NAGLU | NM_000263.4 | c.942C>G | p.Phe314Leu | missense_variant | 5/6 | ENST00000225927.7 | NP_000254.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NAGLU | ENST00000225927.7 | c.942C>G | p.Phe314Leu | missense_variant | 5/6 | 1 | NM_000263.4 | ENSP00000225927 | P1 | |
NAGLU | ENST00000592454.1 | c.39C>G | p.Phe13Leu | missense_variant | 1/2 | 2 | ENSP00000468665 | |||
NAGLU | ENST00000591587.1 | c.360-1901C>G | intron_variant | 5 | ENSP00000467836 | |||||
NAGLU | ENST00000586516.5 | downstream_gene_variant | 2 | ENSP00000467135 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251356Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135856
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461792Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727206
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-B Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2002 | - - |
Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 12, 2024 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 314 of the NAGLU protein (p.Phe314Leu). This variant is present in population databases (rs118204025, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis IIIB (PMID: 12202988, 27243974). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1570). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NAGLU protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
NAGLU-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 14, 2023 | The NAGLU c.942C>G variant is predicted to result in the amino acid substitution p.Phe314Leu. This variant has been reported in the homozygous state or with a second NAGLU variant in individuals with mucopolysaccharidosis type IIIB (Supplementary Table S2, Yubero et al. 2016. PubMed ID: 27243974; Tanaka et al. 2002. PubMed ID: 12202988). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-40693145-C-G). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at