rs398123060
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_001278716.2(FBXL4):c.1703G>C(p.Gly568Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,602 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G568G) has been classified as Likely benign.
Frequency
Consequence
NM_001278716.2 missense, splice_region
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBXL4 | NM_001278716.2 | c.1703G>C | p.Gly568Ala | missense_variant, splice_region_variant | 10/10 | ENST00000369244.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBXL4 | ENST00000369244.7 | c.1703G>C | p.Gly568Ala | missense_variant, splice_region_variant | 10/10 | 1 | NM_001278716.2 | P1 | |
FBXL4 | ENST00000229971.2 | c.1703G>C | p.Gly568Ala | missense_variant, splice_region_variant | 9/9 | 1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.89e-7 AC: 1AN: 1451602Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 722218
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Mitochondrial DNA depletion syndrome 13 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Nov 16, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 05, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The missense variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.52; 3Cnet: 0.96). The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000066092/PMID: 23993194). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23993194, 25868664, 27743463). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Aug 10, 2017 | The NM_012160.4:c.1703G>C (NP_036292.2:p.Gly568Ala) [GRCH38: NC_000006.12:g.98874441C>G] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993194 ; 25868664 ; 27743463 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 13 which is a recessive disorder. PP2:This is a missense variant in FBXL4 with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FBXL4 structure, function, or protein-protein interaction. PP4:Patient’s phenotype or family history is highly specific for FBXL4. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at