rs148412639
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_ModeratePP5
The NM_000379.4(XDH):c.1686+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000925 in 1,613,748 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00057 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00096 ( 1 hom. )
Consequence
XDH
NM_000379.4 splice_donor, intron
NM_000379.4 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.68
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 Uncertain_significance. Variant got 3 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02073963 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8, offset of 9, new splice context is: acgGTcagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PP5
Variant 2-31373872-C-G is Pathogenic according to our data. Variant chr2-31373872-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505602.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| XDH | NM_000379.4 | c.1686+1G>C | splice_donor_variant, intron_variant | ENST00000379416.4 | NP_000370.2 | |||
| XDH | XM_011533095.3 | c.1683+1G>C | splice_donor_variant, intron_variant | XP_011531397.1 | ||||
| XDH | XM_011533096.3 | c.1686+1G>C | splice_donor_variant, intron_variant | XP_011531398.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| XDH | ENST00000379416.4 | c.1686+1G>C | splice_donor_variant, intron_variant | 1 | NM_000379.4 | ENSP00000368727.3 |
Frequencies
GnomAD3 genomes 0.000572 AC: 87AN: 152166Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000466 AC: 117AN: 251112Hom.: 1 AF XY: 0.000472 AC XY: 64AN XY: 135706
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GnomAD4 exome AF: 0.000962 AC: 1406AN: 1461464Hom.: 1 Cov.: 31 AF XY: 0.000901 AC XY: 655AN XY: 727036
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GnomAD4 genome 0.000571 AC: 87AN: 152284Hom.: 1 Cov.: 32 AF XY: 0.000578 AC XY: 43AN XY: 74448
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary xanthinuria type 1 Pathogenic:2Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 11, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 21, 2018 | This variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 16, 2017 | The c.1686+1G>C (NM_000379.3 c.1686+1G>C) variant in XDH has not been reported i n individuals with xanthinuria. This variant has been identified in 0.076% (50/6 5,368) of European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs148412639). Although this variant has been see n in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1 /2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Biallelic loss of function of the XDH gene has been associated with xanthinuria type I. In summary, although additiona l studies are required to fully establish its null effect, the c.1686+1G>C varia nt is likely pathogenic for xanthinuria, type I based upon its predicted functio nal impact. - |
XDH-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 15, 2024 | The XDH c.1686+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in affected individuals, but has been reported as likely pathogenic in a carrier screening study of newborns (Table S2, Ceyhan-Birsoy et al. 2019. PubMed ID: 30609409). This variant is reported in 0.091% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in XDH are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Xanthinuria type II Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2024 | This sequence change affects a donor splice site in intron 16 of the XDH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in XDH are known to be pathogenic (PMID: 9153281). This variant is present in population databases (rs148412639, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with XDH-related conditions. ClinVar contains an entry for this variant (Variation ID: 505602). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2023 | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Has not been previously published as pathogenic or benign in association with xanthinuria to our knowledge; This variant is associated with the following publications: (PMID: 31589614, 30609409, 31980526, 31345219) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
Name
Calibrated prediction
Score
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
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DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at