2-72887471-CG-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_003124.5(SPR):c.43del(p.Ala15ProfsTer100) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000443 in 1,355,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000044 ( 0 hom. )
Consequence
SPR
NM_003124.5 frameshift
NM_003124.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.55
Genes affected
SPR (HGNC:11257): (sepiapterin reductase) This gene encodes an aldo-keto reductase that catalyzes the NADPH-dependent reduction of pteridine derivatives and is important in the biosynthesis of tetrahydrobiopterin (BH4). Mutations in this gene result in DOPA-responsive dystonia due to sepiaterin reductase deficiency. A pseudogene has been identified on chromosome 1. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.949 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-72887471-CG-C is Pathogenic according to our data. Variant chr2-72887471-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3255615.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPR | NM_003124.5 | c.43del | p.Ala15ProfsTer100 | frameshift_variant | 1/3 | ENST00000234454.6 | NP_003115.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPR | ENST00000234454.6 | c.43del | p.Ala15ProfsTer100 | frameshift_variant | 1/3 | 1 | NM_003124.5 | ENSP00000234454 | P1 | |
SPR | ENST00000498749.1 | n.94del | non_coding_transcript_exon_variant | 1/3 | 3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD4 exome AF: 0.00000443 AC: 6AN: 1355408Hom.: 0 Cov.: 31 AF XY: 0.00000448 AC XY: 3AN XY: 669740
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31
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Dopa-responsive dystonia due to sepiapterin reductase deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Breakthrough Genomics, Breakthrough Genomics | May 30, 2021 | This variant is predicted to cause a frameshift and consequent premature termination of the protein (p.Ala15ProfsTer100) and the resultant protein will likely to lack substrate binding domain[Uniprot] of the protein; this will likely result in loss-of-function. Due to the introduction of a premature stop codon, this aberrant transcript will likely be targeted by the nonsense-mediated mRNA decay (NMD) mechanism [PMID: 15040442]. The variant has not been previously reported in the public databases or in the literature. However, in the ClinVar database, several other truncating variants lying downstream of the identified variant, has been previously reported as likely pathogenic/pathogenic in the context of dopa-responsive dystonia due to sepiapterin reductase deficiency. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.