rs1366813

Positions:

• chr2-31347510-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000379.4(XDH):​c.3276+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 1,613,232 control chromosomes in the GnomAD database, including 476,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (43796 hom., cov: 33)
  • Exomes 𝑓: 0.77 (432785 hom.)
• Consequence: XDH NM_000379.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.11

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-31347510-T-C is Benign according to our data. Variant chr2-31347510-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 191300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-31347510-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XDH	NM_000379.4	c.3276+12A>G		intron_variant		ENST00000379416.4	NP_000370.2
XDH	XM_011533095.3	c.3273+12A>G		intron_variant			XP_011531397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4	c.3276+12A>G		intron_variant		1	NM_000379.4	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.758 AC: 115224 AN: 152080 Hom.: 43768 Cov.: 33

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.735

Gnomad ASJ AF: 0.814

Gnomad EAS AF: 0.847

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.764

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.765

Gnomad OTH AF: 0.760

GnomAD3 exomes AF: 0.776 AC: 194993 AN: 251154 Hom.: 75821 AF XY: 0.780 AC XY: 105901 AN XY: 135750

Gnomad AFR exome AF: 0.724

Gnomad AMR exome AF: 0.742

Gnomad ASJ exome AF: 0.816

Gnomad EAS exome AF: 0.851

Gnomad SAS exome AF: 0.833

Gnomad FIN exome AF: 0.757

Gnomad NFE exome AF: 0.768

Gnomad OTH exome AF: 0.766

GnomAD4 exome AF: 0.769 AC: 1123791 AN: 1461034 Hom.: 432785 Cov.: 72 AF XY: 0.772 AC XY: 560782 AN XY: 726858

Gnomad4 AFR exome AF: 0.714

Gnomad4 AMR exome AF: 0.742

Gnomad4 ASJ exome AF: 0.822

Gnomad4 EAS exome AF: 0.857

Gnomad4 SAS exome AF: 0.837

Gnomad4 FIN exome AF: 0.750

Gnomad4 NFE exome AF: 0.763

Gnomad4 OTH exome AF: 0.771

GnomAD4 genome AF: 0.758 AC: 115304 AN: 152198 Hom.: 43796 Cov.: 33 AF XY: 0.758 AC XY: 56436 AN XY: 74420

Gnomad4 AFR AF: 0.726

Gnomad4 AMR AF: 0.734

Gnomad4 ASJ AF: 0.814

Gnomad4 EAS AF: 0.846

Gnomad4 SAS AF: 0.829

Gnomad4 FIN AF: 0.764

Gnomad4 NFE AF: 0.765

Gnomad4 OTH AF: 0.758

Alfa AF: 0.764 Hom.: 12192

Bravo AF: 0.756

Asia WGS AF: 0.792 AC: 2754 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary xanthinuria type 1 Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 31, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2018	- -

Xanthinuria type II Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.14
DANN	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs1366813; hg19: chr2-31570376;