rs587777193
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_001312673.2(PCYT1A):c.990del(p.Ser331ProfsTer166) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000689 in 1,580,936 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P330P) has been classified as Likely benign.
Frequency
Consequence
NM_001312673.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCYT1A | NM_001312673.2 | c.990del | p.Ser331ProfsTer166 | frameshift_variant | 9/9 | ENST00000431016.6 | |
PCYT1A | NM_005017.4 | c.990del | p.Ser331ProfsTer166 | frameshift_variant | 10/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCYT1A | ENST00000431016.6 | c.990del | p.Ser331ProfsTer166 | frameshift_variant | 9/9 | 1 | NM_001312673.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 151912Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000765 AC: 17AN: 222150Hom.: 0 AF XY: 0.0000910 AC XY: 11AN XY: 120944
GnomAD4 exome AF: 0.0000721 AC: 103AN: 1429024Hom.: 0 Cov.: 31 AF XY: 0.0000802 AC XY: 57AN XY: 710552
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 151912Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74186
ClinVar
Submissions by phenotype
Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 02, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Aug 28, 2019 | A heterozygous deletion variant was identified, NM_005017.3(PCYT1A):c.990delC in exon 10 of 10 of the PCYT1A gene. This deletion is predicted to cause a frameshift starting at position 331, introducing a stop codon 165 residues downstream, NP_005008.2(PCYT1A):p.(Ser331Profs*166). The variant is predicted to result in a loss of normal protein function through an extension of the reading frame, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD population database at a frequency of 0.007% (19 heterozygotes, 0 homozygotes). It has been previously reported in patients with Spondylometaphyseal dysplasia with cone-rod dystrophy (ClinVar, Hoover-Fong, J. et al. (2014)). Other variants predicted to cause an extension of the reading frame have been reported as pathogenic in individuals with this condition (Payne, F. et al (2014)). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. - |
Pathogenic, criteria provided, single submitter | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | This sequence change results in a frameshift in the PCYT1A gene (p.Ser331Profs*166). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the PCYT1A protein and extend the protein by 128 additional amino acid residues. This variant is present in population databases (rs587777193, gnomAD 0.02%). This frameshift has been observed in individual(s) with spondylometaphyseal dysplasia with cone-rod dystrophy (PMID: 24387990). ClinVar contains an entry for this variant (Variation ID: 101061). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at