rs118203978
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001371596.2(MFSD8):āc.362A>Gā(p.Tyr121Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,856 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. Y121S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001371596.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MFSD8 | NM_001371596.2 | c.362A>G | p.Tyr121Cys | missense_variant | 4/12 | ENST00000641686.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFSD8 | ENST00000641686.2 | c.362A>G | p.Tyr121Cys | missense_variant | 4/12 | NM_001371596.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461856Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727228
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 7 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2009 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 12, 2021 | This sequence change replaces tyrosine with cysteine at codon 121 of the MFSD8 protein (p.Tyr121Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with late infantile neuronal ceroid lipofuscinoses in 3 siblings (PMID: 18850119). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1004). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect MFSD8 function (PMID: 20826447). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2022 | Identified in a cohort of individuals with epilepsy and neurodevelopmental disorders; however, detailed clinical and segregation data was not provided (Lindy et al., 2018); Published functional studies demonstrate the Y121C variant does not have an effect on protein localization (Sharifi et al, 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20826447, 29655203, 18850119) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at