rs397514513
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_183075.3(CYP2U1):c.947A>T(p.Asp316Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,812 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D316H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_183075.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP2U1 | NM_183075.3 | c.947A>T | p.Asp316Val | missense_variant | 2/5 | ENST00000332884.11 | |
LOC107986298 | XR_001741784.2 | n.204+33294T>A | intron_variant, non_coding_transcript_variant | ||||
CYP2U1 | XM_005262717.2 | c.1001A>T | p.Asp334Val | missense_variant | 2/5 | ||
CYP2U1 | XM_005262720.2 | c.491-1950A>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP2U1 | ENST00000332884.11 | c.947A>T | p.Asp316Val | missense_variant | 2/5 | 1 | NM_183075.3 | P1 | |
CYP2U1-AS1 | ENST00000656249.1 | n.80+33294T>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461812Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727206
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 56 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 01, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 07, 2012 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Apr 30, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 01, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID: 29034544, 28600779, 23176821, ClinVar ID: 39500] - |
Likely pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Nov 24, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 2022 | Published functional studies demonstrate no detectable enzyme activity (Durand et al., 2018); Not present at significant allele frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28600779, 34546337, 25558065, 23176821, 27292318, 29034544, 30202406, 31130284, 27535533, 35046417) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2021 | - - |
Spastic paraplegia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 16, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP2U1 protein function. ClinVar contains an entry for this variant (Variation ID: 39500). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23176821). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 316 of the CYP2U1 protein (p.Asp316Val). - |
Likely pathogenic, no assertion criteria provided | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Dec 01, 2014 | - - |
Neurodegeneration;C0557874:Global developmental delay Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Dec 01, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at