rs119460972

chr2-31386525-G-Achr2-31386525-G-Cchr2-31386525-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000379.4(XDH):c.682C>T(p.Arg228Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

XDH
NM_000379.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.249

Variant links:

Genes affected

XDH (HGNC:12805): (xanthine dehydrogenase) Xanthine dehydrogenase belongs to the group of molybdenum-containing hydroxylases involved in the oxidative metabolism of purines. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Xanthine dehydrogenase can be converted to xanthine oxidase by reversible sulfhydryl oxidation or by irreversible proteolytic modification. Defects in xanthine dehydrogenase cause xanthinuria, may contribute to adult respiratory stress syndrome, and may potentiate influenza infection through an oxygen metabolite-dependent mechanism. [provided by RefSeq, Jan 2014]

XDH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-31386525-G-A is Pathogenic according to our data. Variant chr2-31386525-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
XDH	NM_000379.4 linkuse as main transcript	c.682C>T	p.Arg228Ter	stop_gained	9/36	ENST00000379416.4
XDH	XM_011533095.3 linkuse as main transcript	c.682C>T	p.Arg228Ter	stop_gained	9/36
XDH	XM_011533096.3 linkuse as main transcript	c.682C>T	p.Arg228Ter	stop_gained	9/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XDH	ENST00000379416.4 linkuse as main transcript	c.682C>T	p.Arg228Ter	stop_gained	9/36	1	NM_000379.4	P1
XDH	ENST00000491727.5 linkuse as main transcript	n.225C>T		non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251428

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135884

show subpopulations

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 SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary xanthinuria type 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 10, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 1997	- -

Xanthinuria type II

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 19, 2020

This variant is present in population databases (rs119460972, ExAC 0.01%). This sequence change creates a premature translational stop signal (p.Arg228*) in the XDH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in XDH are known to be pathogenic (PMID: 9153281). This variant has been observed in individual(s) with xanthinuria (PMID: 9153281). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2954). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Uncertain

0.040

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Benign

-0.099

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.16

MutationTaster

Benign

1.0

Vest4

0.92

GERP RS

-2.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over