X-134475197-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000194.3(HPRT1):c.151C>T(p.Arg51*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000194.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HPRT1 | NM_000194.3 | c.151C>T | p.Arg51* | stop_gained | Exon 3 of 9 | ENST00000298556.8 | NP_000185.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HPRT1 | ENST00000298556.8 | c.151C>T | p.Arg51* | stop_gained | Exon 3 of 9 | 1 | NM_000194.3 | ENSP00000298556.7 | ||
HPRT1 | ENST00000462974.5 | n.309C>T | non_coding_transcript_exon_variant | Exon 3 of 8 | 3 | |||||
HPRT1 | ENST00000475720.1 | n.109C>T | non_coding_transcript_exon_variant | Exon 2 of 8 | 3 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1090652Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 356590
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Lesch-Nyhan syndrome Pathogenic:3
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Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as pathogenic (ClinVar ID: VCV000010060.7). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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not provided Pathogenic:2
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Identified in multiple unrelated patients with clinical features consistent with Lesch-Nyhan syndrome in published literature (Oh et al., 2011; Fu et al., 2015; Cho et al., 2019; Madeo et al., 2019); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21331772, 25525159, 25481104, 2323782, 8946118, 31624056, 16336979, 31129767, 31182398, 33584783, 35559039) -
Lesch-Nyhan syndrome;C0268117:Partial hypoxanthine-guanine phosphoribosyltransferase deficiency Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg51*) in the HPRT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPRT1 are known to be pathogenic (PMID: 15571220, 17027311, 22157001). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Lesch-Nyhan disease (PMID: 17027311, 25481104). ClinVar contains an entry for this variant (Variation ID: 10060). For these reasons, this variant has been classified as Pathogenic. -
Microcephaly Uncertain:1
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HPRT FUJIMI Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at