rs724159970
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001371596.2(MFSD8):c.1141G>T(p.Glu381*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,998 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 Pathogenic (★★).
Frequency
Consequence
NM_001371596.2 stop_gained
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 |
---|---|---|---|---|---|---|---|---|
MFSD8 | NM_001371596.2 | c.1141G>T | p.Glu381* | stop_gained | Exon 11 of 12 | ENST00000641686.2 | NP_001358525.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251282Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135820
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727232
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74318
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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Reported in a family with macular dystrophy who had a second MFSD8 missense variant identified; however, none of the affected individuals had any symptoms of neural ceroid lipofuscinosis (NCL) (Roosing et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 19177532, 25227500, 31589614) -
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Macular dystrophy with central cone involvement Pathogenic:2
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This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with neuronal ceroid lipofuscinoses and macular dystrophy [PMID 19177532, 25227500] -
Neuronal ceroid lipofuscinosis 7 Pathogenic:2
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This sequence change creates a premature translational stop signal (p.Glu381*) in the MFSD8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MFSD8 are known to be pathogenic (PMID: 19177532, 25227500, 28586915). This variant is present in population databases (rs724159970, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinoses and macular dystrophy with central cone involvement (PMID: 19177532, 25227500). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162379). For these reasons, this variant has been classified as Pathogenic. -
Neuronal ceroid lipofuscinosis 7;C4015371:Macular dystrophy with central cone involvement Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The p.E381* pathogenic mutation (also known as c.1141G>T), located in coding exon 11 of the MFSD8 gene, results from a G to T substitution at nucleotide position 1141. This changes the amino acid from a glutamic acid to a stop codon within coding exon 11. This variant was reported in an individual with variant late infantile neuronal ceroid lipofuscinosis, who had an additional MFSD8 nonsense variant also detected, although phase information (cis or trans) was not provided (Aiello C et al. Hum. Mutat., 2009 Mar;30:E530-40). This variant was also detected in a family with macular dystrophy where affected family members had p.E381* and an additional MFSD8 missense variant detected in trans (Roosing S et al. Ophthalmology, 2015 Jan;122:170-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Late-infantile neuronal ceroid lipofuscinosis Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at