dbSNP rs1569354918: HPRT1:c.28-2A>G (chrX-134473357-A-G) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000194.3(HPRT1):c.28-2A>G variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

HPRT1
NM_000194.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.32

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.3, offset of 5, new splice context is: atatttctttttcggattAGtga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-134473357-A-G is Pathogenic according to our data. Variant chrX-134473357-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2664053.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.28-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 8	ENST00000298556.8	NP_000185.1	P00492A0A140VJL3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HPRT1	ENST00000298556.8 link	c.28-2A>G	splice_acceptor_variant, intron_variant	Intron 1 of 8	1	NM_000194.3	ENSP00000298556.7	P00492
HPRT1	ENST00000462974.5 link	n.186-2A>G	splice_acceptor_variant, intron_variant	Intron 1 of 7	3
HPRT1	ENST00000475720.1 link	n.-17A>G	upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

969824

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

287544

African (AFR)

AF:

0.00

AC:

AN:

24027

American (AMR)

AF:

0.00

AC:

AN:

35049

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18574

East Asian (EAS)

AF:

0.00

AC:

AN:

29511

South Asian (SAS)

AF:

0.00

AC:

AN:

51363

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40421

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3836

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

725210

Other (OTH)

AF:

0.00

AC:

AN:

41833

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Lesch-Nyhan syndrome

Pathogenic:1

Nov 24, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

FATHMM_MKL

Pathogenic

1.0

PhyloP100

9.3

GERP RS

4.7

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.79

Position offset: 7

DS_AL_spliceai

1.0

Position offset: 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

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over