rs137852486

Positions:

• chrX-134498670-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000194.3(HPRT1):​c.595T>G​(p.Phe199Val) 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 Pathogenic,other (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HPRT1 NM_000194.3 missense
• Clinical Significance: Pathogenic; other no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.52

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a strand (size 3) in uniprot entity HPRT_HUMAN there are 4 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-134498670-T-G is Pathogenic according to our data. Variant chrX-134498670-T-G is described in ClinVar as [Pathogenic, other]. Clinvar id is 10043.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPRT1	NM_000194.3	c.595T>G	p.Phe199Val	missense_variant	8/9	ENST00000298556.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPRT1	ENST00000298556.8	c.595T>G	p.Phe199Val	missense_variant	8/9	1	NM_000194.3	P1
HPRT1	ENST00000475720.1	n.553T>G		non_coding_transcript_exon_variant	7/8	3
HPRT1	ENST00000462974.5			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic; other

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Lesch-Nyhan syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1989

- -

HPRT NEW BRITON Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.93
MutPred		0.90		Loss of catalytic residue at F199 (P = 0.0455);
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.99
gMVP		0.99

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: rs137852486; hg19: chrX-133632700;