rs267606863

Variant names:

• chrX-134498655-G-A
• rs267606863
• NM_000194.3:c.580G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-134498655-G-A
• chrX-134498655-G-C
• chrX-134498655-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000194.3(HPRT1):​c.580G>A​(p.Asp194Asn) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D194E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HPRT1 NM_000194.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.40
• Publications: 9 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics, Orphanet
• hypoxanthine guanine phosphoribosyltransferase partial deficiency

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000194.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-134498657-C-G is described in ClinVar as Pathogenic|other. ClinVar VariationId is 10081.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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, 0.995
• PP5: Variant X-134498655-G-A is Pathogenic according to our data. Variant chrX-134498655-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10037.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.580G>A	p.Asp194Asn	missense	Exon 8 of 9	NP_000185.1	A0A140VJL3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPRT1	ENST00000298556.8	TSL:1 MANE Select	c.580G>A	p.Asp194Asn	missense	Exon 8 of 9	ENSP00000298556.7	P00492
	HPRT1	ENST00000969780.1		c.625G>A	p.Asp209Asn	missense	Exon 9 of 10	ENSP00000639839.1
	HPRT1	ENST00000969779.1		c.616G>A	p.Asp206Asn	missense	Exon 9 of 10	ENSP00000639838.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.97	D
Vest4		0.99
MutPred		0.97		Loss of catalytic residue at D194 (P = 0.1186)
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.93
gMVP		1.0
Mutation Taster		=44/56	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs267606863; hg19: chrX-133632685;