rs137852478

chrX-134475285-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000194.3(HPRT1):c.239A>T(p.Asp80Val) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D80E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HPRT1 NM_000194.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 8.86

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 15) in uniprot entity HPRT_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000194.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-134475285-A-T is Pathogenic according to our data. Variant chrX-134475285-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10030.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.239A>T	p.Asp80Val	missense_variant	3/9	ENST00000298556.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPRT1	ENST00000298556.8	c.239A>T	p.Asp80Val	missense_variant	3/9	1	NM_000194.3	P1
HPRT1	ENST00000462974.5	n.397A>T		non_coding_transcript_exon_variant	3/8	3
HPRT1	ENST00000475720.1	n.197A>T		non_coding_transcript_exon_variant	2/8	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1989

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2021

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. Experimental studies have shown that this variant affects HPRT1 protein function (PMID: 25481104). This variant has been observed in individual(s) with clinical features of HPRT deficiency (PMID: 20176575, 2738157, Invitae). This variant is also known as HPRT Arlington in the literature. ClinVar contains an entry for this variant (Variation ID: 10030). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with valine at codon 80 of the HPRT1 protein (p.Asp80Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. -

HPRT ARLINGTON Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.056	T
Polyphen		0.73	P
Vest4		0.94
MutPred		0.85		Loss of ubiquitination at K83 (P = 0.0734);
MVP		1.0
MPC		3.4
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852478; hg19: chrX-133609315;