chr17-42543997-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The ENST00000225927.7(NAGLU):c.1991C>T(p.Ala664Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000435 in 1,610,258 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A664A) has been classified as Likely benign.
Frequency
Consequence
ENST00000225927.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NAGLU | NM_000263.4 | c.1991C>T | p.Ala664Val | missense_variant | 6/6 | ENST00000225927.7 | NP_000254.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NAGLU | ENST00000225927.7 | c.1991C>T | p.Ala664Val | missense_variant | 6/6 | 1 | NM_000263.4 | ENSP00000225927 | P1 | |
NAGLU | ENST00000591587.1 | c.*960C>T | 3_prime_UTR_variant | 4/4 | 5 | ENSP00000467836 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000412 AC: 1AN: 242476Hom.: 0 AF XY: 0.00000762 AC XY: 1AN XY: 131286
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1458130Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3AN XY: 725006
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152128Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74320
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-B Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Aug 05, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Jan 08, 2022 | A Homozygous missense variation in exon 6 of the NAGLU gene that results in the amino acid substitution of Valine for alanine at codon 664 was detected. The observed variant c.1991C>T (p.Ala664Val) has not been reported in the 1000 genomes and has a MAF of 0.0004% in the gnomAD databases. The in silico prediction of the variant are possibly damaging by LRT, SIFT, PROVEAN and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 20, 2017 | - - |
Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 23, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 664 of the NAGLU protein (p.Ala664Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Sanfilippo syndrome type B (PMID: 9443878). 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: 521840). 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. Experimental studies have shown that this missense change affects NAGLU function (PMID: 9443878, 29979746). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at