NM_000379.4:c.*518A>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

XDH Gene-Disease associations (from GenCC):

• xanthinuria type I

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000379.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	NM_000379.4	MANE Select	c.*518A>G		3_prime_UTR	Exon 36 of 36	NP_000370.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	ENST00000379416.4	TSL:1 MANE Select	c.*518A>G		3_prime_UTR	Exon 36 of 36	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

African (AFR) AF: 0.172 AC: 77 AN: 448

American (AMR) AF: 0.583 AC: 1760 AN: 3020

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 141 AN: 330

East Asian (EAS) AF: 0.592 AC: 803 AN: 1356

South Asian (SAS) AF: 0.477 AC: 1150 AN: 2410

European-Finnish (FIN) AF: 0.633 AC: 233 AN: 368

Middle Eastern (MID) AF: 0.438 AC: 21 AN: 48

European-Non Finnish (NFE) AF: 0.491 AC: 5041 AN: 10270

Other (OTH) AF: 0.487 AC: 436 AN: 896

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

African (AFR) AF: 0.186 AC: 7707 AN: 41532

American (AMR) AF: 0.544 AC: 8315 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1442 AN: 3472

East Asian (EAS) AF: 0.604 AC: 3120 AN: 5168

South Asian (SAS) AF: 0.482 AC: 2327 AN: 4830

European-Finnish (FIN) AF: 0.596 AC: 6296 AN: 10568

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.478 AC: 32468 AN: 67970

Other (OTH) AF: 0.415 AC: 879 AN: 2116

Alfa AF: 0.448 Hom.: 43770

Bravo AF: 0.402

Asia WGS AF: 0.504 AC: 1753 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary xanthinuria type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.0
DANN	Benign	0.80
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042039; hg19: chr2-31558306;