NM_000194.3:c.222C>A

Variant names:

• chrX-134475268-C-A
• rs137852481
• NM_000194.3:c.222C>A

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.222C>A​(p.Phe74Leu) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F74C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HPRT1 NM_000194.3 missense
• Clinical Significance: Pathogenic; other no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.34
• Publications: 16 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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-134475267-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 804086.Status of the report is criteria_provided_single_submitter, 1 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, 0.991
• PP5: Variant X-134475268-C-A is Pathogenic according to our data. Variant chrX-134475268-C-A is described in ClinVar as Pathogenic|other. ClinVar VariationId is 10036.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPRT1	NM_000194.3	c.222C>A	p.Phe74Leu	missense_variant	Exon 3 of 9	ENST00000298556.8	NP_000185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPRT1	ENST00000298556.8	c.222C>A	p.Phe74Leu	missense_variant	Exon 3 of 9	1	NM_000194.3	ENSP00000298556.7
HPRT1	ENST00000462974.5	n.380C>A		non_coding_transcript_exon_variant	Exon 3 of 8	3
HPRT1	ENST00000475720.1	n.180C>A		non_coding_transcript_exon_variant	Exon 2 of 8	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic; other

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Lesch-Nyhan syndrome Pathogenic:1

Oct 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HPRT FLINT Other:1

Sep 26, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.92		Loss of catalytic residue at F74 (P = 0.0826);
MVP		1.0
MPC		2.7
ClinPred		0.99	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs137852481; hg19: chrX-133609298; COSMIC: COSV53777024;