chrX-134475218-G-A

Position:

• chrX-134475218-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000194.3(HPRT1):​c.172G>A​(p.Gly58Arg) 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: 22)
• Consequence: HPRT1 NM_000194.3 missense
• Clinical Significance: Pathogenic; other no assertion criteria provided P:1 O: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 Likely_pathogenic. Variant got 7 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant X-134475218-G-A is Pathogenic according to our data. Variant chrX-134475218-G-A is described in ClinVar as [Pathogenic, other]. Clinvar id is 10075.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPRT1	NM_000194.3	c.172G>A	p.Gly58Arg	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.172G>A	p.Gly58Arg	missense_variant	3/9	1	NM_000194.3	ENSP00000298556	P1
HPRT1	ENST00000462974.5	n.330G>A		non_coding_transcript_exon_variant	3/8	3
HPRT1	ENST00000475720.1	n.130G>A		non_coding_transcript_exon_variant	2/8	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic; other

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Partial hypoxanthine-guanine phosphoribosyltransferase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1991

- -

HPRT TOOWONG Other:1

other, no assertion criteria provided

literature only

OMIM

May 12, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.79
Sift	Benign	0.030	D
Sift4G	Benign	0.070	T
Polyphen		0.029	B
Vest4		0.90
MutPred		0.63		Gain of solvent accessibility (P = 0.0037);
MVP		1.0
MPC		2.3
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.97

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: rs137852500; hg19: chrX-133609248;