2-72891406-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_003124.5(SPR):c.655C>T(p.Arg219Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,114 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. R219R) has been classified as Likely benign.
Frequency
Consequence
NM_003124.5 stop_gained
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 |
---|---|---|---|---|---|---|---|
SPR | NM_003124.5 | c.655C>T | p.Arg219Ter | stop_gained | 3/3 | ENST00000234454.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPR | ENST00000234454.6 | c.655C>T | p.Arg219Ter | stop_gained | 3/3 | 1 | NM_003124.5 | P1 | |
SPR | ENST00000498749.1 | n.600C>T | non_coding_transcript_exon_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152104Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251456Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135914
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727246
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74420
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 08, 2023 | Nonsense variant predicted to result in protein truncation, as the last 43 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 31589614, 22291068, 34324503) - |
Dopa-responsive dystonia due to sepiapterin reductase deficiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
Pathogenic, criteria provided, single submitter | research | Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics | Apr 10, 2020 | - - |
Dystonic disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 09, 2023 | ClinVar contains an entry for this variant (Variation ID: 235551). This premature translational stop signal has been observed in individual(s) with sepiapterin reductase deficiency and/or SPR-related conditions (PMID: 22291068, 34324503). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs779204655, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg219*) in the SPR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the SPR protein. This variant disrupts a region of the SPR protein in which other variant(s) (p.Lys251*) have been determined to be pathogenic (PMID: 16917893, 18502672, 21431957, 21677200, 24212389, 25763508, 29116116). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at