Genetic Variant NM_000194.3:c.329C>A (chrX-134486475-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_000194.3(HPRT1):c.329C>A(p.Ser110*) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 20)

Exomes 𝑓: 9.9e-7 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

HPRT1
NM_000194.3 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.63

Publications

7 publications found

Variant links:

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)

HPRT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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.329C>A	p.Ser110*	stop_gained	Exon 4 of 9	NP_000185.1	A0A140VJL3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HPRT1	ENST00000298556.8	TSL:1 MANE Select	c.329C>A	p.Ser110*	stop_gained	Exon 4 of 9	ENSP00000298556.7	P00492
HPRT1	ENST00000969780.1		c.374C>A	p.Ser125*	stop_gained	Exon 5 of 10	ENSP00000639839.1
HPRT1	ENST00000969779.1		c.329C>A	p.Ser110*	stop_gained	Exon 4 of 10	ENSP00000639838.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

101431

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.89e-7

AC:

AN:

1011591

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

304485

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24713

American (AMR)

AF:

0.00

AC:

AN:

34289

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18396

East Asian (EAS)

AF:

0.00

AC:

AN:

29095

South Asian (SAS)

AF:

0.00

AC:

AN:

50060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39429

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3411

European-Non Finnish (NFE)

AF:

0.00000130

AC:

AN:

769407

Other (OTH)

AF:

0.00

AC:

AN:

42791

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

101431

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

26563

African (AFR)

AF:

0.00

AC:

AN:

27470

American (AMR)

AF:

0.00

AC:

AN:

9147

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2551

East Asian (EAS)

AF:

0.00

AC:

AN:

3288

South Asian (SAS)

AF:

0.00

AC:

AN:

2256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3933

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

50578

Other (OTH)

AF:

0.00

AC:

AN:

1334

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.96

PhyloP100

5.6

Vest4

0.91

GERP RS

5.3

Mutation Taster

=1/199

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.43

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.43

Position offset: -10

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over