rs137852485

Variant names:

• chrX-134475358-C-A
• rs137852485
• NM_000194.3:c.312C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-134475358-C-A
• chrX-134475358-C-T

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.312C>A​(p.Ser104Arg) variant causes a missense change involving the alteration of a non-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).

• 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: 0.950
• Publications: 8 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 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
• 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, 0.993
• PP5: Variant X-134475358-C-A is Pathogenic according to our data. Variant chrX-134475358-C-A is described in ClinVar as Pathogenic|other. ClinVar VariationId is 10042.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.312C>A	p.Ser104Arg	missense	Exon 3 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.312C>A	p.Ser104Arg	missense	Exon 3 of 9	ENSP00000298556.7	P00492
	HPRT1	ENST00000969780.1		c.357C>A	p.Ser119Arg	missense	Exon 4 of 10	ENSP00000639839.1
	HPRT1	ENST00000969779.1		c.312C>A	p.Ser104Arg	missense	Exon 3 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: 1011521 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 295445

African (AFR) AF: 0.00 AC: 0 AN: 24849

American (AMR) AF: 0.00 AC: 0 AN: 34937

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18809

East Asian (EAS) AF: 0.00 AC: 0 AN: 29869

South Asian (SAS) AF: 0.00 AC: 0 AN: 51720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3927

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 763607

Other (OTH) AF: 0.00 AC: 0 AN: 43333

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic; other

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.73
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		0.95
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.94		Gain of MoRF binding (P = 0.0672)
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.99
gMVP		0.99
Mutation Taster		=22/78	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137852485; hg19: chrX-133609388;