chrX-134486475-C-T

Variant names:

• chrX-134486475-C-T
• rs137852482
• NM_000194.3:c.329C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM1 PP2 PP3_Moderate PP5_Moderate

The NM_000194.3(HPRT1):​c.329C>T​(p.Ser110Leu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004571483: Experimental studies have shown that this missense change affects HPRT1 function (PMID:22157001).".

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000020 (0 hom. 1 hem.)
• Consequence: HPRT1 NM_000194.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 5.63
• Publications: 7 publications found

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]

HPRT1 Gene-Disease associations (from GenCC):

• Lesch-Nyhan syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics, Orphanet
• hypoxanthine guanine phosphoribosyltransferase partial deficiency

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004571483: Experimental studies have shown that this missense change affects HPRT1 function (PMID: 22157001).
• PM1: In a chain Hypoxanthine-guanine phosphoribosyltransferase (size 216) in uniprot entity HPRT_HUMAN there are 52 pathogenic changes around while only 1 benign (98%) in NM_000194.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.3178 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Lesch-Nyhan syndrome, hypoxanthine guanine phosphoribosyltransferase partial deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant X-134486475-C-T is Pathogenic according to our data. Variant chrX-134486475-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 10038.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000194.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPRT1	NM_000194.3	MANE Select	c.329C>T	p.Ser110Leu	missense	Exon 4 of 9	NP_000185.1	A0A140VJL3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPRT1	ENST00000298556.8	TSL:1 MANE Select	c.329C>T	p.Ser110Leu	missense	Exon 4 of 9	ENSP00000298556.7	P00492
	HPRT1	ENST00000969780.1		c.374C>T	p.Ser125Leu	missense	Exon 5 of 10	ENSP00000639839.1
	HPRT1	ENST00000969779.1		c.329C>T	p.Ser110Leu	missense	Exon 4 of 10	ENSP00000639838.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000198 AC: 2 AN: 1011610 Hom.: 0 Cov.: 19 AF XY: 0.00000328 AC XY: 1 AN XY: 304498

African (AFR) AF: 0.00 AC: 0 AN: 24713

American (AMR) AF: 0.00 AC: 0 AN: 34290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18396

East Asian (EAS) AF: 0.00 AC: 0 AN: 29095

South Asian (SAS) AF: 0.00 AC: 0 AN: 50062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3411

European-Non Finnish (NFE) AF: 0.00000260 AC: 2 AN: 769421

Other (OTH) AF: 0.00 AC: 0 AN: 42792

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Lesch-Nyhan syndrome;C0268117:Partial hypoxanthine-guanine phosphoribosyltransferase deficiency (1)
1	-	-	Partial hypoxanthine-guanine phosphoribosyltransferase deficiency (1)
-	-	-	HPRT LONDON (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		5.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.54		Loss of relative solvent accessibility (P = 0.0186)
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.85
Mutation Taster		=57/43	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -10

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

Other links and lift over

dbSNP: rs137852482; hg19: chrX-133620505;