chrX-134475194-G-C

Position:

• chrX-134475194-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000194.3(HPRT1):​c.148G>C​(p.Ala50Pro) 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. A50V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HPRT1 NM_000194.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.50

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 12 ACMG points.

• PM1: In a chain Hypoxanthine-guanine phosphoribosyltransferase (size 216) in uniprot entity HPRT_HUMAN there are 37 pathogenic changes around while only 0 benign (100%) in NM_000194.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-134475194-G-C is Pathogenic according to our data. Variant chrX-134475194-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521480.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPRT1	NM_000194.3	c.148G>C	p.Ala50Pro	missense_variant	3/9	ENST00000298556.8	NP_000185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPRT1	ENST00000298556.8	c.148G>C	p.Ala50Pro	missense_variant	3/9	1	NM_000194.3	ENSP00000298556.7
HPRT1	ENST00000462974.5	n.306G>C		non_coding_transcript_exon_variant	3/8	3
HPRT1	ENST00000475720.1	n.106G>C		non_coding_transcript_exon_variant	2/8	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephrolithiasis/nephrocalcinosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2019

The p.A50P variant (also known as c.148G>C), located in coding exon 3 of the HPRT1 gene, results from a G to C substitution at nucleotide position 148. The alanine at codon 50 is replaced by proline, an amino acid with highly similar properties. In one study, this alteration was detected in an individual with HGprt-related neurological dysfunction (HND). In addition, authors used fibroblast cultures to show that both Hprt and Hprt enzyme activity for this alteration was significantly reduced (less than 2%) compared to normal controls (Fu R et al. Mol. Genet. Metab., 2015 Jan;114:55-61). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.5	H
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.95		Gain of disorder (P = 0.0394);
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		4.7
Varity_R		1.0
gMVP		1.0

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: rs1556026984; hg19: chrX-133609224;