rs1042039

Variant names:

• chr2-31335440-T-C
• rs1042039
• NM_000379.4:c.*518A>G

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.*518A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 171,280 control chromosomes in the GnomAD database, including 17,404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14774 hom., cov: 32)
  • Exomes 𝑓: 0.50 (2630 hom.)
• Consequence: XDH NM_000379.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.456

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=-0.85).
• BP6: Variant 2-31335440-T-C is Benign according to our data. Variant chr2-31335440-T-C is described in ClinVar as [Benign]. Clinvar id is 335751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XDH	NM_000379.4	c.*518A>G		3_prime_UTR_variant	Exon 36 of 36	ENST00000379416.4	NP_000370.2
XDH	XM_011533095.3	c.*518A>G		3_prime_UTR_variant	Exon 36 of 36		XP_011531397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416	c.*518A>G		3_prime_UTR_variant	Exon 36 of 36	1	NM_000379.4	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62986 AN: 152016 Hom.: 14776 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.414

GnomAD4 exome AF: 0.505 AC: 9662 AN: 19146 Hom.: 2630 Cov.: 0 AF XY: 0.505 AC XY: 4982 AN XY: 9860

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.583

Gnomad4 ASJ exome AF: 0.427

Gnomad4 EAS exome AF: 0.592

Gnomad4 SAS exome AF: 0.477

Gnomad4 FIN exome AF: 0.633

Gnomad4 NFE exome AF: 0.491

Gnomad4 OTH exome AF: 0.487

GnomAD4 genome AF: 0.414 AC: 62997 AN: 152134 Hom.: 14774 Cov.: 32 AF XY: 0.424 AC XY: 31537 AN XY: 74378

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.544

Gnomad4 ASJ AF: 0.415

Gnomad4 EAS AF: 0.604

Gnomad4 SAS AF: 0.482

Gnomad4 FIN AF: 0.596

Gnomad4 NFE AF: 0.478

Gnomad4 OTH AF: 0.415

Alfa AF: 0.463 Hom.: 28173

Bravo AF: 0.402

Asia WGS AF: 0.504 AC: 1753 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary xanthinuria type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.0
DANN	Benign	0.80

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: rs1042039; hg19: chr2-31558306;