chrX-134473377-G-C

Variant names:

• chrX-134473377-G-C
• rs137852499
• NM_000194.3:c.46G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_000194.3(HPRT1):​c.46G>C​(p.Gly16Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000094 in 1,064,320 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G16S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: HPRT1 NM_000194.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 0 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 9 ACMG points.

• PM1: In a chain Hypoxanthine-guanine phosphoribosyltransferase (size 216) in uniprot entity HPRT_HUMAN there are 49 pathogenic changes around while only 1 benign (98%) 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-134473377-G-A is described in ClinVar as Pathogenic|other. ClinVar VariationId is 10074.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, 0.938

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.46G>C	p.Gly16Arg	missense	Exon 2 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.46G>C	p.Gly16Arg	missense	Exon 2 of 9	ENSP00000298556.7
	HPRT1	ENST00000462974.5	TSL:3	n.204G>C		non_coding_transcript_exon	Exon 2 of 8
	HPRT1	ENST00000475720.1	TSL:3	n.4G>C		non_coding_transcript_exon	Exon 1 of 8

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.40e-7 AC: 1 AN: 1064320 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 336870

African (AFR) AF: 0.00 AC: 0 AN: 25767

American (AMR) AF: 0.00 AC: 0 AN: 35162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19130

East Asian (EAS) AF: 0.00 AC: 0 AN: 29974

South Asian (SAS) AF: 0.00 AC: 0 AN: 53369

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4035

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 811382

Other (OTH) AF: 0.0000222 AC: 1 AN: 45029

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.73
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		10
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.68		Gain of solvent accessibility (P = 0.0171)
MVP		0.99
MPC		3.1
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.96
gMVP		0.98
Mutation Taster		=5/95	disease causing

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: rs137852499; hg19: chrX-133607407;