X-134473357-A-G

Variant names:

• chrX-134473357-A-G
• rs1569354918
• NM_000194.3:c.28-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000194.3(HPRT1):​c.28-2A>G variant causes a splice acceptor, intron 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 Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: HPRT1 NM_000194.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• 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]

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.3, offset of 5, new splice context is: atatttctttttcggattAGtga. 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
• PP5: Variant X-134473357-A-G is Pathogenic according to our data. Variant chrX-134473357-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2664053.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPRT1	NM_000194.3	c.28-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 8	ENST00000298556.8	NP_000185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPRT1	ENST00000298556.8	c.28-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 8	1	NM_000194.3	ENSP00000298556.7
HPRT1	ENST00000462974.5	n.186-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 7	3
HPRT1	ENST00000475720.1	n.-17A>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 969824 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 287544

African (AFR) AF: 0.00 AC: 0 AN: 24027

American (AMR) AF: 0.00 AC: 0 AN: 35049

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18574

East Asian (EAS) AF: 0.00 AC: 0 AN: 29511

South Asian (SAS) AF: 0.00 AC: 0 AN: 51363

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40421

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3836

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 725210

Other (OTH) AF: 0.00 AC: 0 AN: 41833

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lesch-Nyhan syndrome Pathogenic:1

Nov 24, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.3
GERP RS		4.7
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.79		Position offset: 7
DS_AL_spliceai		1.0		Position offset: 2

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

Publications

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Other links and lift over

dbSNP: rs1569354918; hg19: chrX-133607387;