rs207440

chr2-31339546-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000379.4(XDH):c.3717G>A(p.Glu1239=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0575 in 1,614,126 control chromosomes in the GnomAD database, including 2,861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (230 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2631 hom.)
• Consequence: XDH NM_000379.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.552

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-31339546-C-T is Benign according to our data. Variant chr2-31339546-C-T is described in ClinVar as [Benign]. Clinvar id is 255970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.552 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XDH	NM_000379.4	c.3717G>A	p.Glu1239=	synonymous_variant	34/36	ENST00000379416.4
XDH	XM_011533095.3	c.3714G>A	p.Glu1238=	synonymous_variant	34/36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XDH	ENST00000379416.4	c.3717G>A	p.Glu1239=	synonymous_variant	34/36	1	NM_000379.4	P1

Frequencies

GnomAD3 genomes AF: 0.0523 AC: 7958 AN: 152130 Hom.: 230 Cov.: 32

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0318

Gnomad ASJ AF: 0.0438

Gnomad EAS AF: 0.00541

Gnomad SAS AF: 0.0694

Gnomad FIN AF: 0.0425

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0591

Gnomad OTH AF: 0.0483

GnomAD3 exomes AF: 0.0491 AC: 12346 AN: 251484 Hom.: 379 AF XY: 0.0519 AC XY: 7055 AN XY: 135914

Gnomad AFR exome AF: 0.0567

Gnomad AMR exome AF: 0.0218

Gnomad ASJ exome AF: 0.0425

Gnomad EAS exome AF: 0.00375

Gnomad SAS exome AF: 0.0733

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0596

Gnomad OTH exome AF: 0.0525

GnomAD4 exome AF: 0.0580 AC: 84827 AN: 1461878 Hom.: 2631 Cov.: 33 AF XY: 0.0587 AC XY: 42661 AN XY: 727242

Gnomad4 AFR exome AF: 0.0593

Gnomad4 AMR exome AF: 0.0232

Gnomad4 ASJ exome AF: 0.0434

Gnomad4 EAS exome AF: 0.00685

Gnomad4 SAS exome AF: 0.0732

Gnomad4 FIN exome AF: 0.0387

Gnomad4 NFE exome AF: 0.0614

Gnomad4 OTH exome AF: 0.0568

GnomAD4 genome AF: 0.0523 AC: 7965 AN: 152248 Hom.: 230 Cov.: 32 AF XY: 0.0507 AC XY: 3777 AN XY: 74426

Gnomad4 AFR AF: 0.0569

Gnomad4 AMR AF: 0.0318

Gnomad4 ASJ AF: 0.0438

Gnomad4 EAS AF: 0.00542

Gnomad4 SAS AF: 0.0692

Gnomad4 FIN AF: 0.0425

Gnomad4 NFE AF: 0.0591

Gnomad4 OTH AF: 0.0483

Alfa AF: 0.0570 Hom.: 510

Bravo AF: 0.0510

Asia WGS AF: 0.0560 AC: 194 AN: 3478

EpiCase AF: 0.0595

EpiControl AF: 0.0607

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	Genome-Nilou Lab	Dec 05, 2021	- -
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. -

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

Mar 07, 2020

- -

Xanthinuria type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	6.6
Dann	Benign	0.56

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: rs207440; hg19: chr2-31562412; COSMIC: COSV65150411;