rs119460972
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.Arg228*) 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
NM_000379.4 stop_gained
Scores
1
2
4
Clinical Significance
Conservation
PhyloP100: 0.249
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]
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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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
XDH | NM_000379.4 | c.682C>T | p.Arg228* | stop_gained | 9/36 | ENST00000379416.4 | NP_000370.2 | |
XDH | XM_011533095.3 | c.682C>T | p.Arg228* | stop_gained | 9/36 | XP_011531397.1 | ||
XDH | XM_011533096.3 | c.682C>T | p.Arg228* | stop_gained | 9/29 | XP_011531398.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
XDH | ENST00000379416.4 | c.682C>T | p.Arg228* | stop_gained | 9/36 | 1 | NM_000379.4 | ENSP00000368727.3 | ||
XDH | ENST00000491727.5 | n.225C>T | non_coding_transcript_exon_variant | 4/6 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251428Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135884
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727240
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74288
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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 | Labcorp Genetics (formerly Invitae), Labcorp | 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
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
GERP RS
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at