X-134490192-T-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_000194.3(HPRT1):c.389T>A(p.Val130Asp) variant causes a missense change. 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)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

HPRT1
NM_000194.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 6.99

Publications

6 publications found

Variant links:

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

HPRT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000194.3

PM2

Very rare variant in population databases, with high coverage;

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, 0.994

PP5

Variant X-134490192-T-A is Pathogenic according to our data. Variant chrX-134490192-T-A is described in ClinVar as Pathogenic|other. ClinVar VariationId is 10040.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPRT1	NM_000194.3 link	c.389T>A	p.Val130Asp	missense_variant	Exon 5 of 9	ENST00000298556.8	NP_000185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HPRT1	ENST00000298556.8 link	c.389T>A	p.Val130Asp	missense_variant	Exon 5 of 9	1	NM_000194.3	ENSP00000298556.7
HPRT1	ENST00000462974.5 link	n.547T>A		non_coding_transcript_exon_variant	Exon 5 of 8	3
HPRT1	ENST00000475720.1 link	n.347T>A		non_coding_transcript_exon_variant	Exon 4 of 8	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

928895

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

271371

African (AFR)

AF:

0.00

AC:

AN:

23304

American (AMR)

AF:

0.00

AC:

AN:

33401

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17592

East Asian (EAS)

AF:

0.00

AC:

AN:

28535

South Asian (SAS)

AF:

0.00

AC:

AN:

49157

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3651

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

695330

Other (OTH)

AF:

0.00

AC:

AN:

39779

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lesch-Nyhan syndrome

Pathogenic:2

Mar 01, 1989

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Feb 11, 2025

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 3384338). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.87 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with HPRT1-related disorder (ClinVar ID: VCV000010040 /PMID: 3265398 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

HPRT MIDLAND

Other:1

Sep 26, 2017

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.72

BayesDel_noAF

Pathogenic

0.79

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.6

PhyloP100

7.0

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.3

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.99

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.99

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over