rs13415401

Variant names:

• chr2-31348375-G-C
• rs13415401
• NM_000379.4:c.3052-12C>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.3052-12C>G variant causes a 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 intron
• Scores: Splicing: ADA: 0.0001073
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.363
• Publications: 12 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 255969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	NM_000379.4	MANE Select	c.3052-12C>G		intron	N/A	NP_000370.2	P47989

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	ENST00000379416.4	TSL:1 MANE Select	c.3052-12C>G		intron	N/A	ENSP00000368727.3	P47989
	XDH	ENST00000879520.1		c.3160-12C>G		intron	N/A	ENSP00000549579.1
	XDH	ENST00000879524.1		c.3061-12C>G		intron	N/A	ENSP00000549583.1

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

GnomAD2 exomes AF: 0.773 AC: 193212 AN: 249888 AF XY: 0.777

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 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

African (AFR) AF: 0.689 AC: 23060 AN: 33462

American (AMR) AF: 0.740 AC: 33040 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.822 AC: 21487 AN: 26128

East Asian (EAS) AF: 0.856 AC: 33975 AN: 39688

South Asian (SAS) AF: 0.827 AC: 71257 AN: 86184

European-Finnish (FIN) AF: 0.752 AC: 40121 AN: 53376

Middle Eastern (MID) AF: 0.785 AC: 4524 AN: 5766

European-Non Finnish (NFE) AF: 0.762 AC: 847288 AN: 1111348

Other (OTH) AF: 0.768 AC: 46339 AN: 60346

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

African (AFR) AF: 0.701 AC: 29091 AN: 41498

American (AMR) AF: 0.731 AC: 11188 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 2825 AN: 3468

East Asian (EAS) AF: 0.844 AC: 4369 AN: 5174

South Asian (SAS) AF: 0.816 AC: 3931 AN: 4818

European-Finnish (FIN) AF: 0.768 AC: 8123 AN: 10582

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.764 AC: 51944 AN: 67990

Other (OTH) AF: 0.749 AC: 1581 AN: 2112

Alfa AF: 0.763 Hom.: 8119

Bravo AF: 0.748

Asia WGS AF: 0.770 AC: 2680 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary xanthinuria type 1 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Xanthinuria type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	14
DANN	Benign	0.47
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13415401; hg19: chr2-31571241; COSMIC: COSV105313738;