chr4-127920743-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001371596.2(MFSD8):c.1444C>T(p.Arg482*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000198 in 1,613,902 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 (★★).
Frequency
Consequence
NM_001371596.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MFSD8 | NM_001371596.2 | c.1444C>T | p.Arg482* | stop_gained | Exon 12 of 12 | ENST00000641686.2 | NP_001358525.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152044Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251364Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135860
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461858Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18AN XY: 727240
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74270
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 7 Pathogenic:4
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This sequence change creates a premature translational stop signal (p.Arg482*) in the MFSD8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the MFSD8 protein. This variant is present in population databases (rs724159971, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with variant-late infantile neuronal ceroid lipofuscinosis (VL-NCL) and neuronal ceroid lipofuscinosis (PMID: 19177532, 25976102, 28708303; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162382). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
peripheric neuropathy; global cerebral atrophy; epilepsy (myoclonia); severe regression of acquisitions starting at 3 years old -
Neuronal ceroid lipofuscinosis 7;C4015371:Macular dystrophy with central cone involvement Pathogenic:2
PM2_Supporting+PVS1_Moderate+PM3_VeryStrong+PP4 -
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Inborn genetic diseases Pathogenic:1
The p.R482* variant (also known as c.1444C>T), located in coding exon 12 of the MFSD8 gene, results from a C to T substitution at nucleotide position 1444. This changes the amino acid from an arginine to a stop codon within coding exon 12. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of MFSD8, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 37 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. This alteration has been reported in children with variant-late infantile form of NCL (v-LINCL); in one case, a second pathogenic variant was detected however parental testing was not performed to confirm phase (Aiello C et al. Hum. Mutat., 2009 Mar;30:E530-40); in another, the p.R482* variant was confirmed in trans with a second disease causing allele (Chérot E et al. Clin. Genet., 2018 Mar;93:567-576). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
not provided Pathogenic:1
Reported in association with variant late-infantile neuronal ceroid lipofucinosis (Aiello et al., 2009; Kousi et al., 2012).; Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 37 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22668694, 21990111, 19177532, 28708303, 31105743, 33726816) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at