Genetic Variant HPRT1:p.Ala2Ser (chrX-134460315-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP2BP4

The NM_000194.3(HPRT1):c.4G>T(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000354 in 1,131,098 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000020 ( 0 hom. 1 hem. )

Consequence

HPRT1
NM_000194.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a modified_residue N-acetylalanine (size 0) in uniprot entity HPRT_HUMAN

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). GenCC associations: The gene is linked to Lesch-Nyhan syndrome, hypoxanthine guanine phosphoribosyltransferase partial deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.3826848).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPRT1	NM_000194.3 link	c.4G>T	p.Ala2Ser	missense_variant	Exon 1 of 9	ENST00000298556.8	NP_000185.1	P00492A0A140VJL3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPRT1	ENST00000298556.8 link	c.4G>T	p.Ala2Ser	missense_variant	Exon 1 of 9	1	NM_000194.3	ENSP00000298556.7		P00492
HPRT1	ENST00000462974.5 link	n.-36G>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

113087

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000185

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

85410

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000196

AC:

AN:

1018011

Hom.:

Cov.:

AF XY:

0.00000304

AC XY:

AN XY:

329261

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22305

American (AMR)

AF:

0.00

AC:

AN:

27434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17536

East Asian (EAS)

AF:

0.00

AC:

AN:

24403

South Asian (SAS)

AF:

0.00

AC:

AN:

48396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25599

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3055

European-Non Finnish (NFE)

AF:

0.00000124

AC:

AN:

806703

Other (OTH)

AF:

0.0000235

AC:

AN:

42580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000177

AC:

AN:

113087

Hom.:

Cov.:

AF XY:

0.0000283

AC XY:

AN XY:

35381

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31291

American (AMR)

AF:

0.000185

AC:

AN:

10821

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3555

South Asian (SAS)

AF:

0.00

AC:

AN:

2834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6209

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53269

Other (OTH)

AF:

0.00

AC:

AN:

1533

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lesch-Nyhan syndrome;C0268117:Partial hypoxanthine-guanine phosphoribosyltransferase deficiency

Uncertain:1

Jan 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.35

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.38

M_CAP

Pathogenic

1.0

MetaRNN

Benign

0.38

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.2

PhyloP100

1.6

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.13

REVEL

Uncertain

0.31

Sift

Benign

0.47

Sift4G

Benign

0.73

Polyphen

0.0040

Vest4

0.20

MutPred

0.13

Gain of phosphorylation at A2 (P = 0.0267);

MVP

0.69

MPC

1.4

ClinPred

0.15

GERP RS

1.4

PromoterAI

-0.36

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.64

Mutation Taster

=92/8

polymorphism

(source)

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

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X-134460315-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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