X-134486514-C-A

Variant names:

• chrX-134486514-C-A
• rs369065223
• NM_000194.3:c.368C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_000194.3(HPRT1):​c.368C>A​(p.Ser123*) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: HPRT1 NM_000194.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.63
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000194.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPRT1	NM_000194.3	MANE Select	c.368C>A	p.Ser123*	stop_gained	Exon 4 of 9	NP_000185.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPRT1	ENST00000298556.8	TSL:1 MANE Select	c.368C>A	p.Ser123*	stop_gained	Exon 4 of 9	ENSP00000298556.7
	HPRT1	ENST00000462974.5	TSL:3	n.526C>A		non_coding_transcript_exon	Exon 4 of 8
	HPRT1	ENST00000475720.1	TSL:3	n.326C>A		non_coding_transcript_exon	Exon 3 of 8

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1043731 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 320453

African (AFR) AF: 0.00 AC: 0 AN: 25352

American (AMR) AF: 0.00 AC: 0 AN: 34919

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18791

East Asian (EAS) AF: 0.00 AC: 0 AN: 29566

South Asian (SAS) AF: 0.00 AC: 0 AN: 52533

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39915

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3874

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 794667

Other (OTH) AF: 0.00 AC: 0 AN: 44114

GnomAD4 genome Cov.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		5.6
Vest4		0.87
GERP RS		5.3
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.44		Position offset: 16

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

Other links and lift over

dbSNP: rs369065223; hg19: chrX-133620544; COSMIC: COSV100053233;