rs754875934
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_152419.3(HGSNAT):c.370A>T(p.Arg124Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,600,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R124K) has been classified as Uncertain significance.
Frequency
Consequence
NM_152419.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HGSNAT | NM_152419.3 | c.370A>T | p.Arg124Trp | missense_variant, splice_region_variant | 3/18 | ENST00000379644.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HGSNAT | ENST00000379644.9 | c.370A>T | p.Arg124Trp | missense_variant, splice_region_variant | 3/18 | 2 | NM_152419.3 | P3 | |
HGSNAT | ENST00000520704.1 | c.220A>T | p.Arg74Trp | missense_variant, splice_region_variant, NMD_transcript_variant | 3/10 | 1 | |||
HGSNAT | ENST00000517319.1 | c.235-213A>T | intron_variant, NMD_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000208 AC: 5AN: 240818Hom.: 0 AF XY: 0.0000306 AC XY: 4AN XY: 130602
GnomAD4 exome AF: 0.0000186 AC: 27AN: 1448212Hom.: 0 Cov.: 31 AF XY: 0.0000237 AC XY: 17AN XY: 718558
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74366
ClinVar
Submissions by phenotype
Retinitis pigmentosa 73 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 29, 2022 | This variant was identified as compound heterozygous with NM_152419.3:c.1843G>A._x000D_ Criteria applied: PS3, PM3_STR, PM2_SUP - |
Mucopolysaccharidosis, MPS-III-C Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 11, 2021 | NM_152419.2(HGSNAT):c.370A>T(R124W) is a missense variant classified as a variant of uncertain significance in the context of mucopolysaccharidosis type IIIC. R124W has not been observed in cases with relevant disease. Functional assessments of this variant are available in the literature (PMID: 25859010). R124W has been observed in population frequency databases (gnomAD ASJ 0.02%). In summary, there is insufficient evidence to classify NM_152419.2(HGSNAT):c.370A>T(R124W) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 124 of the HGSNAT protein (p.Arg124Trp). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs754875934, gnomAD 0.02%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 25859010; Invitae). ClinVar contains an entry for this variant (Variation ID: 208815). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in partial skipping of exon 3 and introduces a premature termination codon (PMID: 25859010). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 28, 2022 | Missense variant demonstrated to result in partial exon skipping in a gene for which loss-of-function is a known mechanism of disease (Haer-Wigman et al., 2015); This variant is associated with the following publications: (PMID: 25859010, 31456290, 32770643, 34426522) - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 18, 2019 | - - |
Retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at