X-134500030-C-T

Variant names:

• chrX-134500030-C-T
• rs137852490
• NM_000194.3:c.610C>T

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.610C>T​(p.His204Tyr) variant causes a missense, splice region 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 predict no significant impact on normal splicing. 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. H204R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: HPRT1 NM_000194.3 missense, splice_region
• Scores: Splicing: ADA: 0.8320
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.22

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, 0.989
• PP5: Variant X-134500030-C-T is Pathogenic according to our data. Variant chrX-134500030-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 654514.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.610C>T	p.His204Tyr	missense_variant, splice_region_variant	Exon 9 of 9	ENST00000298556.8	NP_000185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPRT1	ENST00000298556.8	c.610C>T	p.His204Tyr	missense_variant, splice_region_variant	Exon 9 of 9	1	NM_000194.3	ENSP00000298556.7
HPRT1	ENST00000475720.1	n.567+1346C>T		intron_variant	Intron 7 of 7	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1037930 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 321564

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine with tyrosine at codon 204 of the HPRT1 protein (p.His204Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Lesch-Nyhan syndrome (PMID: 9799086). This variant is also known as p.His203Tyr in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.His204 (also known as p.His203 in the literature) amino acid residue in HPRT1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 16549399, 2928313, 22157001, 25481104, 2071157, 23975452), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.91
MutPred		0.87		Loss of helix (P = 0.1706);
MVP		1.0
MPC		2.0
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.080		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: rs137852490; hg19: chrX-133634060;