rs13415401

chr2-31348375-G-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.3052-12C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,613,090 control chromosomes in the GnomAD database, including 473,636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42913 hom., cov: 33)
  • Exomes 𝑓: 0.77 (430723 hom.)
• Consequence: XDH NM_000379.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001073
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.363

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=-0.83).
• BP6: Variant 2-31348375-G-C is Benign according to our data. Variant chr2-31348375-G-C is described in ClinVar as [Benign]. Clinvar id is 255969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-31348375-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XDH	NM_000379.4	c.3052-12C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000379416.4
XDH	XM_011533095.3	c.3049-12C>G		splice_polypyrimidine_tract_variant, intron_variant
XDH	XM_011533096.3	c.3052-12C>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XDH	ENST00000379416.4	c.3052-12C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000379.4	P1

Frequencies

GnomAD3 genomes AF: 0.750 AC: 114019 AN: 152026 Hom.: 42897 Cov.: 33

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.845

Gnomad SAS AF: 0.816

Gnomad FIN AF: 0.768

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.751

GnomAD3 exomes AF: 0.773 AC: 193212 AN: 249888 Hom.: 74764 AF XY: 0.777 AC XY: 104925 AN XY: 135054

Gnomad AFR exome AF: 0.700

Gnomad AMR exome AF: 0.740

Gnomad ASJ exome AF: 0.816

Gnomad EAS exome AF: 0.849

Gnomad SAS exome AF: 0.822

Gnomad FIN exome AF: 0.759

Gnomad NFE exome AF: 0.767

Gnomad OTH exome AF: 0.763

GnomAD4 exome AF: 0.767 AC: 1121091 AN: 1460946 Hom.: 430723 Cov.: 37 AF XY: 0.770 AC XY: 559291 AN XY: 726770

Gnomad4 AFR exome AF: 0.689

Gnomad4 AMR exome AF: 0.740

Gnomad4 ASJ exome AF: 0.822

Gnomad4 EAS exome AF: 0.856

Gnomad4 SAS exome AF: 0.827

Gnomad4 FIN exome AF: 0.752

Gnomad4 NFE exome AF: 0.762

Gnomad4 OTH exome AF: 0.768

GnomAD4 genome AF: 0.750 AC: 114084 AN: 152144 Hom.: 42913 Cov.: 33 AF XY: 0.751 AC XY: 55839 AN XY: 74372

Gnomad4 AFR AF: 0.701

Gnomad4 AMR AF: 0.731

Gnomad4 ASJ AF: 0.815

Gnomad4 EAS AF: 0.844

Gnomad4 SAS AF: 0.816

Gnomad4 FIN AF: 0.768

Gnomad4 NFE AF: 0.764

Gnomad4 OTH AF: 0.749

Alfa AF: 0.763 Hom.: 8119

Bravo AF: 0.748

Asia WGS AF: 0.770 AC: 2680 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary xanthinuria type 1 Benign:2

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-Nilou Lab	Dec 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2018

- -

Xanthinuria type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	14
Dann	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.066
SpliceAI score (max)		0.010		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: rs13415401; hg19: chr2-31571241; COSMIC: COSV105313738;