X-134486475-C-T

Variant names:

• chrX-134486475-C-T
• rs137852482
• NM_000194.3:c.329C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PP2 PP3_Moderate PP5_Moderate

The NM_000194.3(HPRT1):​c.329C>T​(p.Ser110Leu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000020 (0 hom. 1 hem.)
• Consequence: HPRT1 NM_000194.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 5.63

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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a chain Hypoxanthine-guanine phosphoribosyltransferase (size 216) in uniprot entity HPRT_HUMAN there are 86 pathogenic changes around while only 1 benign (99%) in NM_000194.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.3178 (below the threshold of 3.09). GenCC associations: The gene is linked to Lesch-Nyhan syndrome, hypoxanthine guanine phosphoribosyltransferase partial deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant X-134486475-C-T is Pathogenic according to our data. Variant chrX-134486475-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10038.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPRT1	NM_000194.3	c.329C>T	p.Ser110Leu	missense_variant	Exon 4 of 9	ENST00000298556.8	NP_000185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPRT1	ENST00000298556.8	c.329C>T	p.Ser110Leu	missense_variant	Exon 4 of 9	1	NM_000194.3	ENSP00000298556.7
HPRT1	ENST00000462974.5	n.487C>T		non_coding_transcript_exon_variant	Exon 4 of 8	3
HPRT1	ENST00000475720.1	n.287C>T		non_coding_transcript_exon_variant	Exon 3 of 8	3

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000198 AC: 2 AN: 1011610 Hom.: 0 Cov.: 19 AF XY: 0.00000328 AC XY: 1 AN XY: 304498

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 24713

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 34290

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 18396

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 29095

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 50062

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 39430

Gnomad4 NFE exome AF: 0.00000260 AC: 2 AN: 769421

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 42792

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Partial hypoxanthine-guanine phosphoribosyltransferase deficiency Pathogenic:1

Sep 01, 1983

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Jul 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 110 of the HPRT1 protein (p.Ser110Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypoxanthine-guanine phosphoribosyltransferase deficiency (PMID: 3198771). This variant is also known as HPRT(London). ClinVar contains an entry for this variant (Variation ID: 10038). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HPRT1 function (PMID: 22157001). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

HPRT LONDON Other:1

Sep 10, 2020

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.6	H
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.54		Loss of relative solvent accessibility (P = 0.0186);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.85
Mutation Taster		=57/43	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -10

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852482; hg19: chrX-133620505;