rs747260038
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000317.3(PTS):βc.118_121delβ(p.Phe40GlyfsTer17) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000439 in 1,595,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L39L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000317.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTS | NM_000317.3 | c.118_121del | p.Phe40GlyfsTer17 | frameshift_variant | 2/6 | ENST00000280362.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTS | ENST00000280362.8 | c.118_121del | p.Phe40GlyfsTer17 | frameshift_variant | 2/6 | 1 | NM_000317.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000682 AC: 1AN: 146526Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247390Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134032
GnomAD4 exome AF: 0.00000414 AC: 6AN: 1449290Hom.: 0 AF XY: 0.00000555 AC XY: 4AN XY: 721200
GnomAD4 genome ? AF: 0.00000682 AC: 1AN: 146526Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 70864
ClinVar
Submissions by phenotype
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 24, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change creates a premature translational stop signal (p.Phe40Glyfs*17) in the PTS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTS are known to be pathogenic (PMID: 3297709, 16917893). This variant is present in population databases (rs747260038, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with 6-pyruvoyl-tetrahydropterin synthase deficiency (PMID: 23138986). ClinVar contains an entry for this variant (Variation ID: 550850). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2018 | The c.118_121delTTTG variant in the PTS gene has been reported previously using alternate nomenclature (c.116_119del) in a heterozygous individual with mild hyperphenylalaninemia and no identifiable second variant (Liu et al., 2001). The variant has also been reported in a female infant with PTPSD who harbored a second PTS variant (Ye et al., 2013). The c.118_121delTTTG variant causes a frameshift starting with codon Phenylalanine 40, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Phe40GlyfsX17. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.118_121delTTTG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.118_121delTTTG as a pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at