rs786200980
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000194.3(HPRT1):c.212dupG(p.Tyr72fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
HPRT1
NM_000194.3 frameshift
NM_000194.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.659
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-134475252-A-AG is Pathogenic according to our data. Variant chrX-134475252-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 167181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HPRT1 | NM_000194.3 | c.212dupG | p.Tyr72fs | frameshift_variant | 3/9 | ENST00000298556.8 | NP_000185.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HPRT1 | ENST00000298556.8 | c.212dupG | p.Tyr72fs | frameshift_variant | 3/9 | 1 | NM_000194.3 | ENSP00000298556.7 | ||
HPRT1 | ENST00000462974.5 | n.370dupG | non_coding_transcript_exon_variant | 3/8 | 3 | |||||
HPRT1 | ENST00000475720.1 | n.170dupG | non_coding_transcript_exon_variant | 2/8 | 3 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1081215Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 347679
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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27
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347679
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GnomAD4 genome Cov.: 22
GnomAD4 genome
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22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Lesch-Nyhan syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1989 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4,PP5. This variant was detected in hemizygous state. - |
Lesch-Nyhan syndrome;C0268117:Partial hypoxanthine-guanine phosphoribosyltransferase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 29, 2019 | Loss-of-function variants in HPRT1 are known to be pathogenic (PMID: 15571220, 17027311, 22157001). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in several individuals affected with HPRT1-related conditions (PMID: 2928313, 23975452, Invitae). ClinVar contains an entry for this variant (Variation ID: 167181). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr72Leufs*2) in the HPRT1 gene. It is expected to result in an absent or disrupted protein product. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 23, 2014 | - - |
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