X-134473344-A-G

Variant names:

• chrX-134473344-A-G
• rs867788976
• NM_000194.3:c.28-15A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000194.3(HPRT1):​c.28-15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000096 in 937,767 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000097 (0 hom. 2 hem.)
• Consequence: HPRT1 NM_000194.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.37
• 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, G2P, Orphanet, Labcorp Genetics (formerly Invitae), 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant X-134473344-A-G is Benign according to our data. Variant chrX-134473344-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2922505.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

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.28-15A>G		intron	N/A	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.28-15A>G		intron	N/A	ENSP00000298556.7	P00492
	HPRT1	ENST00000969780.1		c.28-15A>G		intron	N/A	ENSP00000639839.1
	HPRT1	ENST00000969779.1		c.28-15A>G		intron	N/A	ENSP00000639838.1

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112104 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183048 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000969 AC: 8 AN: 825663 Hom.: 0 Cov.: 15 AF XY: 0.00000844 AC XY: 2 AN XY: 236879

African (AFR) AF: 0.00 AC: 0 AN: 21273

American (AMR) AF: 0.00 AC: 0 AN: 34874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17659

East Asian (EAS) AF: 0.0000347 AC: 1 AN: 28856

South Asian (SAS) AF: 0.00 AC: 0 AN: 48666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40287

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3583

European-Non Finnish (NFE) AF: 0.0000118 AC: 7 AN: 593512

Other (OTH) AF: 0.00 AC: 0 AN: 36953

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112104 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34266

African (AFR) AF: 0.00 AC: 0 AN: 30877

American (AMR) AF: 0.00 AC: 0 AN: 10504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3607

South Asian (SAS) AF: 0.00 AC: 0 AN: 2743

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6045

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53250

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Lesch-Nyhan syndrome;C0268117:Partial hypoxanthine-guanine phosphoribosyltransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.023
DANN	Benign	0.77
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs867788976; hg19: chrX-133607374;