rs104894280
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000317.3(PTS):c.286G>A(p.Asp96Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,122 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 (★★). Synonymous variant affecting the same amino acid position (i.e. D96D) has been classified as Likely benign.
Frequency
Consequence
NM_000317.3 missense
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 |
---|---|---|---|---|---|---|---|
PTS | NM_000317.3 | c.286G>A | p.Asp96Asn | missense_variant | 5/6 | ENST00000280362.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTS | ENST00000280362.8 | c.286G>A | p.Asp96Asn | missense_variant | 5/6 | 1 | NM_000317.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251410Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135878
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461822Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727214
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74492
ClinVar
Submissions by phenotype
6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 17, 2017 | - - |
Pathogenic, no assertion criteria provided | curation | SingHealth Duke-NUS Institute of Precision Medicine | Jun 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 14, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Sep 16, 2020 | The PTS c.286G>A variant is classified as PATHOGENIC (PM3-Very Strong, PS3, PM2, PP4-Moderate). The PTS c.286G>A is a single nucleotide change from a guanine to an adenine at position 286 which is predicted to change the amino acid aspartate in the protein to an asparagine. This variant is one of the most common PTS variants in East Asia and has been previously reported in over 20 patients with 6-pyruvoyl-tetrahydropterin synthase deficiency, including one homozygote (PMID: 10319579,11694255, 11916314, 23138986) (PM3 – Very Strong). Experimental studies have shown that this missense change results in a PTS protein with 10% normal enzyme activity (PMID: 10319579) (PS3). The variant has been reported in dbSNP (rs104894280) but is absent from population databases (PM2). The variant has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 484).The biochemical and clinical features of this patient is consistent with PTPS deficiency (PP4-Moderate). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 96 of the PTS protein (p.Asp96Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with biopterin deficient hyperphenylalanemia (PMID: 10319579, 11694255, 11916314, 18505119, 22237589, 23138986). ClinVar contains an entry for this variant (Variation ID: 484). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PTS function (PMID: 10319579). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1998 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 06, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 07, 2023 | Variant summary: PTS c.286G>A (p.Asp96Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251410 control chromosomes. c.286G>A has been reported in the literature in multiple individuals affected with 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency (example: Imamura_1999, Liu_1998, Cao_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10% of normal activity (Imamura_1999). The following publications have been ascertained in the context of this evaluation (PMID: 25456745, 10319579, 9450907 ). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at