NM_000194.3:c.602A>G

Variant names:

• chrX-134498677-A-G
• rs137852479
• NM_000194.3:c.602A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000194.3(HPRT1):​c.602A>G​(p.Asp201Gly) 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. Variant has been reported in ClinVar as Pathogenic,other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D201Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: HPRT1 NM_000194.3 missense
• Clinical Significance: Pathogenic; other no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.76
• Publications: 6 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 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000194.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.994
• PP5: Variant X-134498677-A-G is Pathogenic according to our data. Variant chrX-134498677-A-G is described in ClinVar as Pathogenic|other. ClinVar VariationId is 10031.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.602A>G	p.Asp201Gly	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.602A>G	p.Asp201Gly	missense	Exon 8 of 9	ENSP00000298556.7	P00492
	HPRT1	ENST00000969780.1		c.647A>G	p.Asp216Gly	missense	Exon 9 of 10	ENSP00000639839.1
	HPRT1	ENST00000969779.1		c.638A>G	p.Asp213Gly	missense	Exon 9 of 10	ENSP00000639838.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1022589 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 303285

African (AFR) AF: 0.00 AC: 0 AN: 24999

American (AMR) AF: 0.00 AC: 0 AN: 35122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18911

East Asian (EAS) AF: 0.00 AC: 0 AN: 29920

South Asian (SAS) AF: 0.00 AC: 0 AN: 52329

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3855

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 773333

Other (OTH) AF: 0.00 AC: 0 AN: 43606

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic; other

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Partial hypoxanthine-guanine phosphoribosyltransferase deficiency (1)
-	-	-	HPRT ASHVILLE (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.029	D
Polyphen		0.95	P
Vest4		0.93
MutPred		0.92		Loss of stability (P = 0.0059)
MVP		1.0
MPC		3.3
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.99
gMVP		0.97
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs137852479; hg19: chrX-133632707;