chrX-134473378-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000194.3(HPRT1):​c.47G>T​(p.Gly16Val) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G16S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

HPRT1
NM_000194.3 missense

Scores

13
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 10.0
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a chain Hypoxanthine-guanine phosphoribosyltransferase (size 216) in uniprot entity HPRT_HUMAN there are 84 pathogenic changes around while only 1 benign (99%) 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 chrX-134473377-G-A is described in ClinVar as [Pathogenic, other]. Clinvar id is 10074.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.95
PP5
Variant X-134473378-G-T is Pathogenic according to our data. Variant chrX-134473378-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 431129.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HPRT1NM_000194.3 linkuse as main transcriptc.47G>T p.Gly16Val missense_variant 2/9 ENST00000298556.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HPRT1ENST00000298556.8 linkuse as main transcriptc.47G>T p.Gly16Val missense_variant 2/91 NM_000194.3 P1
HPRT1ENST00000462974.5 linkuse as main transcriptn.205G>T non_coding_transcript_exon_variant 2/83
HPRT1ENST00000475720.1 linkuse as main transcriptn.5G>T non_coding_transcript_exon_variant 1/83

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
25
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Lesch-Nyhan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGroupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de ParisJan 06, 2017Intellectual disability, severe; tetradystonia; axial hypotonia; small degree of elevated uricemia -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.75
BayesDel_addAF
Pathogenic
0.70
D
BayesDel_noAF
Pathogenic
0.76
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
3.0
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-7.3
D
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.012
D
Polyphen
1.0
D
Vest4
0.91
MutPred
0.75
Loss of disorder (P = 0.0519);
MVP
1.0
MPC
3.2
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.97
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1135401801; hg19: chrX-133607408; API