NM_000194.3:c.368C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_000194.3(HPRT1):c.368C>T(p.Ser123Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000192 in 1,043,737 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 20)

Exomes 𝑓: 0.0000019 ( 0 hom. 0 hem. )

Consequence

HPRT1
NM_000194.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.63

Publications

1 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: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a chain Hypoxanthine-guanine phosphoribosyltransferase (size 216) in uniprot entity HPRT_HUMAN there are 49 pathogenic changes around while only 1 benign (98%) 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, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPRT1	NM_000194.3 link	c.368C>T	p.Ser123Leu	missense_variant	Exon 4 of 9	ENST00000298556.8	NP_000185.1	P00492A0A140VJL3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HPRT1	ENST00000298556.8 link	c.368C>T	p.Ser123Leu	missense_variant	Exon 4 of 9	1	NM_000194.3	ENSP00000298556.7	P00492
HPRT1	ENST00000462974.5 link	n.526C>T		non_coding_transcript_exon_variant	Exon 4 of 8	3
HPRT1	ENST00000475720.1 link	n.326C>T		non_coding_transcript_exon_variant	Exon 3 of 8	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000555

AC:

AN:

180205

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000192

AC:

AN:

1043737

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

320459

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25352

American (AMR)

AF:

0.00

AC:

AN:

34919

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18791

East Asian (EAS)

AF:

0.00

AC:

AN:

29566

South Asian (SAS)

AF:

0.00

AC:

AN:

52533

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39914

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3874

European-Non Finnish (NFE)

AF:

0.00000252

AC:

AN:

794674

Other (OTH)

AF:

0.00

AC:

AN:

44114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.77

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.5

PhyloP100

5.6

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-4.4

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.019

Polyphen

0.047

Vest4

0.50

MVP

0.98

MPC

2.4

ClinPred

0.82

GERP RS

5.3

Varity_R

0.94

gMVP

0.81

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.27

Position offset: 16

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

Computational scores

Splicing

Publications

Other links and lift over