rs387906428

Variant names:

• chrX-134500062-AAAATACAAAGCCTAAGATGAG-A
• rs387906428
• NM_000194.3:c.644_*7delAATACAAAGCCTAAGATGAGA

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM4 PP5

The NM_000194.3(HPRT1):​c.644_*7delAATACAAAGCCTAAGATGAGA​(p.Lys215_Ter219delins???) variant causes a stop lost, conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic,other (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HPRT1 NM_000194.3 stop_lost, conservative_inframe_deletion
• Clinical Significance: Pathogenic; other no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.52
• 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, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypoxanthine guanine phosphoribosyltransferase partial deficiency

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a chain Hypoxanthine-guanine phosphoribosyltransferase (size 216) in uniprot entity HPRT_HUMAN there are 51 pathogenic changes around while only 1 benign (98%) in NM_000194.3
• PM4: Stoplost variant in NM_000194.3 Downstream stopcodon found after 267 codons.
• PP5: Variant X-134500062-AAAATACAAAGCCTAAGATGAG-A is Pathogenic according to our data. Variant chrX-134500062-AAAATACAAAGCCTAAGATGAG-A is described in ClinVar as Pathogenic|other. ClinVar VariationId is 10035.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPRT1	NM_000194.3	MANE Select	c.644_*7delAATACAAAGCCTAAGATGAGA	p.Lys215_Ter219delins???	stop_lost conservative_inframe_deletion	Exon 9 of 9	NP_000185.1
	HPRT1	NM_000194.3	MANE Select	c.644_*7delAATACAAAGCCTAAGATGAGA		3_prime_UTR	Exon 9 of 9	NP_000185.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPRT1	ENST00000298556.8	TSL:1 MANE Select	c.644_*7delAATACAAAGCCTAAGATGAGA	p.Lys215_Ter219delins???	stop_lost conservative_inframe_deletion	Exon 9 of 9	ENSP00000298556.7
	HPRT1	ENST00000298556.8	TSL:1 MANE Select	c.644_*7delAATACAAAGCCTAAGATGAGA		3_prime_UTR	Exon 9 of 9	ENSP00000298556.7
	HPRT1	ENST00000969780.1		c.689_*7delAATACAAAGCCTAAGATGAGA	p.Lys230_Ter234delins???	stop_lost conservative_inframe_deletion	Exon 10 of 10	ENSP00000639839.1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic; other

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Lesch-Nyhan syndrome (1)
-	-	-	HPRT EVANSVILLE (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.5
Mutation Taster		=18/182	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs387906428; hg19: chrX-133634092;