X-134473353-T-C

Variant names:

• chrX-134473353-T-C
• NM_000194.3:c.28-6T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000194.3(HPRT1):​c.28-6T>C variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: HPRT1 NM_000194.3 splice_region, intron
• Scores: Splicing: ADA: 0.01248
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPRT1	NM_000194.3	c.28-6T>C		splice_region_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.28-6T>C		splice_region_variant, intron_variant	Intron 1 of 8	1	NM_000194.3	ENSP00000298556.7
HPRT1	ENST00000462974.5	n.186-6T>C		splice_region_variant, intron_variant	Intron 1 of 7	3
HPRT1	ENST00000475720.1	n.-21T>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 941151 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 274465

African (AFR) AF: 0.00 AC: 0 AN: 23486

American (AMR) AF: 0.00 AC: 0 AN: 35034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18372

East Asian (EAS) AF: 0.00 AC: 0 AN: 29394

South Asian (SAS) AF: 0.00 AC: 0 AN: 50816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3784

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 698997

Other (OTH) AF: 0.00 AC: 0 AN: 40864

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lesch-Nyhan syndrome;C0268117:Partial hypoxanthine-guanine phosphoribosyltransferase deficiency Uncertain:1

Feb 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.96
PhyloP100		8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.012
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

hg19: chrX-133607383;