X-134473357-A-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate
The NM_000194.3(HPRT1):c.28-2A>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 23)
Consequence
HPRT1
NM_000194.3 splice_acceptor
NM_000194.3 splice_acceptor
Scores
3
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.32
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 16 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.2, offset of 5, new splice context is: atatttctttttctgattAGtga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant X-134473357-A-T is Pathogenic according to our data. Variant chrX-134473357-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 10057.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.28-2A>T | splice_acceptor_variant | ENST00000298556.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HPRT1 | ENST00000298556.8 | c.28-2A>T | splice_acceptor_variant | 1 | NM_000194.3 | P1 | |||
HPRT1 | ENST00000462974.5 | n.186-2A>T | splice_acceptor_variant, non_coding_transcript_variant | 3 | |||||
HPRT1 | ENST00000475720.1 | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 19
GnomAD4 exome
Cov.:
19
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
HPRT1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 06, 2023 | Variant summary: HPRT1 c.28-2A>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site and three predict the variant also creates a new 3' acceptor site downstream. Publications have reported experimental evidence that this variant indeed affects mRNA splicing, resulting in the deletion of exon 2 (Gibbs_1990, Del Bigio_2007). The variant was absent in 183054 control chromosomes (gnomAD). c.28-2A>T has been reported in the literature as a de novo occurrence in a male individual affected with Lesch-Nyhan disease (hypoxanthine guanine phosphoribosyltransferase deficiency) whose mother did not carry the variant (Gibbs_1990, Del Bigio_2007). These data suggest the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17483691, 2347587). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Lesch-Nyhan syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1990 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 7
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at