rs1556030169
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_000194.3(HPRT1):c.609dup(p.His204SerfsTer6) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 24)
Consequence
HPRT1
NM_000194.3 frameshift, splice_region
NM_000194.3 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0270
Genes affected
HPRT1 (HGNC:5157): (hypoxanthine phosphoribosyltransferase 1) The protein encoded by this gene is a transferase, which catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate via transfer of the 5-phosphoribosyl group from 5-phosphoribosyl 1-pyrophosphate. This enzyme plays a central role in the generation of purine nucleotides through the purine salvage pathway. Mutations in this gene result in Lesch-Nyhan syndrome or gout.[provided by RefSeq, Jun 2009]
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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 is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-134498683-A-AT is Pathogenic according to our data. Variant chrX-134498683-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 526797.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HPRT1 | NM_000194.3 | c.609dup | p.His204SerfsTer6 | frameshift_variant, splice_region_variant | 8/9 | ENST00000298556.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HPRT1 | ENST00000298556.8 | c.609dup | p.His204SerfsTer6 | frameshift_variant, splice_region_variant | 8/9 | 1 | NM_000194.3 | P1 | |
HPRT1 | ENST00000475720.1 | n.567dup | splice_region_variant, non_coding_transcript_exon_variant | 7/8 | 3 | ||||
HPRT1 | ENST00000462974.5 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Cov.: 23
GnomAD4 exome
Cov.:
23
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Lesch-Nyhan syndrome;C0268117:Partial hypoxanthine-guanine phosphoribosyltransferase deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2017 | This sequence change results in a premature translational stop signal in the HPRT1 gene (p.His204Serfs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acids of the HPRT1 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HPRT1-related disease. Several different truncations (p.Cys206*, p.Gly212*, p.Tyr216*) that lie downstream of this variant have been reported in individuals affected with Lesch-Nyhan syndrome (PMID: 22132984, 11018746, 28045594). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
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Calibrated prediction
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Splicing
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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