rs672601245

Positions:

• chrX-134500026-ATA-TTT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP3 PP5

The NM_000194.3(HPRT1):​c.610-4_610-2delinsTTT variant causes a splice acceptor, splice polypyrimidine tract, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HPRT1 NM_000194.3 splice_acceptor, splice_polypyrimidine_tract, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.45

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.97108066 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of 17, new splice context is: ttgcatgtttgtgtcattAGtga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-134500026-ATA-TTT is Pathogenic according to our data. Variant chrX-134500026-ATA-TTT is described in ClinVar as [Pathogenic]. Clinvar id is 10055.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPRT1	NM_000194.3	c.610-4_610-2delinsTTT		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000298556.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPRT1	ENST00000298556.8	c.610-4_610-2delinsTTT		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000194.3	P1
HPRT1	ENST00000475720.1	n.567+1342_567+1344delinsTTT		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lesch-Nyhan syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1990

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		3.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs672601245; hg19: chrX-133634056;