NM_000194.3:c.-321T>G

Variant names:

• chrX-134459991-T-G
• rs6634990
• NM_000194.3:c.-321T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000194.3(HPRT1):​c.-321T>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 108,661 control chromosomes in the GnomAD database, including 11,491 homozygotes. There are 15,279 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (11491 hom., 15279 hem., cov: 21)
• Consequence: HPRT1 NM_000194.3 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.15
• 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: 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPRT1	NM_000194.3	c.-321T>G		upstream_gene_variant		ENST00000298556.8	NP_000185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPRT1	ENST00000298556.8	c.-321T>G		upstream_gene_variant		1	NM_000194.3	ENSP00000298556.7

Frequencies

GnomAD3 genomes AF: 0.501 AC: 54412 AN: 108611 Hom.: 11491 Cov.: 21

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.653

Gnomad SAS AF: 0.425

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.497

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.501 AC: 54463 AN: 108661 Hom.: 11491 Cov.: 21 AF XY: 0.491 AC XY: 15279 AN XY: 31105

African (AFR) AF: 0.786 AC: 23490 AN: 29877

American (AMR) AF: 0.554 AC: 5673 AN: 10247

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 872 AN: 2624

East Asian (EAS) AF: 0.653 AC: 2174 AN: 3331

South Asian (SAS) AF: 0.426 AC: 1071 AN: 2516

European-Finnish (FIN) AF: 0.364 AC: 2006 AN: 5507

Middle Eastern (MID) AF: 0.295 AC: 61 AN: 207

European-Non Finnish (NFE) AF: 0.349 AC: 18197 AN: 52208

Other (OTH) AF: 0.495 AC: 735 AN: 1486

Alfa AF: 0.401 Hom.: 13112

Bravo AF: 0.536

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 03, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.48
DANN	Benign	0.24
PhyloP100		-4.2
PromoterAI		0.089	Neutral

Splicing

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

Other links and lift over

dbSNP: rs6634990; hg19: chrX-133594021;