chr5-78839372-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000046.5(ARSB):āc.1197C>Gā(p.Phe399Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,550 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 Likely pathogenic (ā ā ).
Frequency
Consequence
NM_000046.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARSB | NM_000046.5 | c.1197C>G | p.Phe399Leu | missense_variant | Exon 6 of 8 | ENST00000264914.10 | NP_000037.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.1197C>G | p.Phe399Leu | missense_variant | Exon 6 of 8 | 1 | NM_000046.5 | ENSP00000264914.4 | ||
ARSB | ENST00000396151.7 | c.1197C>G | p.Phe399Leu | missense_variant | Exon 7 of 8 | 1 | ENSP00000379455.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251354Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135836
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461550Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727092
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:5
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This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 399 of the ARSB protein (p.Phe399Leu). This variant is present in population databases (rs200793396, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 11802522, 18486607, 25190157). ClinVar contains an entry for this variant (Variation ID: 559688). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ARSB protein function. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: ARSB c.1197C>G (p.Phe399Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251354 control chromosomes. c.1197C>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (Yang_2001, Lin_2008, Zheng_2014, He_2021, Fang_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34813777, 33985463, 18486607, 11802522, 25190157). ClinVar contains an entry for this variant (Variation ID: 559688). Based on the evidence outlined above, the variant was classified as pathogenic. -
In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in ExAC (PM2) -
The ARSB c.1197C>G (p.Phe399Leu) missense variant has been reported in five studies and is found in a total of seven individuals with mucopolysaccharidosis, type VI, including in one in a homozygous state and in six in a compound heterozygous state, including one sibling pair (Yang et al. 2001; Ching-Wan et al. 2004; Lin et al. 2008; But et al. 2011; Zheng et al. 2014). The p.Phe399Leu variant was also found in a heterozygous state in two unaffected parents (Ching-Wan et al. 2004). The p.Phe399Leu variant was absent from 150 control subjects and is reported at a frequency of 0.000174 in the East Asian population of the Genome Aggregation Database. Based on the evidence, the p.Phe399Leu variant is classified as pathogenic for mucopolysaccharidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at