rs796052749
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001371596.2(MFSD8):āc.291G>Cā(p.Trp97Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,972 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 ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W97L) has been classified as Uncertain significance.
Frequency
Consequence
NM_001371596.2 missense
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 |
---|---|---|---|---|---|---|---|
MFSD8 | NM_001371596.2 | c.291G>C | p.Trp97Cys | missense_variant | 4/12 | ENST00000641686.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFSD8 | ENST00000641686.2 | c.291G>C | p.Trp97Cys | missense_variant | 4/12 | NM_001371596.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152102Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727236
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74300
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 7 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 14, 2022 | This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 97 of the MFSD8 protein (p.Trp97Cys). This variant is present in population databases (rs796052749, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with MFSD8-related conditions. ClinVar contains an entry for this variant (Variation ID: 206169). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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. - |
Uncertain significance, criteria provided, single submitter | research | Duke University Health System Sequencing Clinic, Duke University Health System | Apr 20, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2015 | p.Trp97Cys (W97C) TGG>TGC: c.291 G>C in exon 5 of the MFSD8 gene (NM_152778.2). The W97C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W97C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, other missense mutations in nearby residues have not been reported. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant The variant is found in MFSD8 panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at