rs206801

Variant names:

• chr2-31405880-G-A
• rs206801
• NM_000379.4:c.100+27C>T

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.100+27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 1,613,112 control chromosomes in the GnomAD database, including 2,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (453 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1715 hom.)
• Consequence: XDH NM_000379.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.283
• Publications: 4 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=-0.84).
• BP6: Variant 2-31405880-G-A is Benign according to our data. Variant chr2-31405880-G-A is described in ClinVar as Benign. ClinVar VariationId is 1271082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XDH	NM_000379.4	c.100+27C>T		intron_variant	Intron 2 of 35	ENST00000379416.4	NP_000370.2
XDH	XM_011533095.3	c.100+27C>T		intron_variant	Intron 2 of 35		XP_011531397.1
XDH	XM_011533096.3	c.100+27C>T		intron_variant	Intron 2 of 28		XP_011531398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4	c.100+27C>T		intron_variant	Intron 2 of 35	1	NM_000379.4	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.0635 AC: 9648 AN: 151924 Hom.: 451 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0604

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0540

Gnomad SAS AF: 0.0619

Gnomad FIN AF: 0.00841

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.0633

GnomAD2 exomes AF: 0.0475 AC: 11931 AN: 251372 AF XY: 0.0473

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0333

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.0569

Gnomad FIN exome AF: 0.00989

Gnomad NFE exome AF: 0.0361

Gnomad OTH exome AF: 0.0501

GnomAD4 exome AF: 0.0419 AC: 61155 AN: 1461070 Hom.: 1715 Cov.: 31 AF XY: 0.0424 AC XY: 30835 AN XY: 726910

African (AFR) AF: 0.128 AC: 4290 AN: 33444

American (AMR) AF: 0.0344 AC: 1539 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3228 AN: 26120

East Asian (EAS) AF: 0.0616 AC: 2447 AN: 39694

South Asian (SAS) AF: 0.0581 AC: 5009 AN: 86232

European-Finnish (FIN) AF: 0.0108 AC: 576 AN: 53412

Middle Eastern (MID) AF: 0.0966 AC: 557 AN: 5768

European-Non Finnish (NFE) AF: 0.0363 AC: 40357 AN: 1111306

Other (OTH) AF: 0.0522 AC: 3152 AN: 60370

GnomAD4 genome AF: 0.0635 AC: 9659 AN: 152042 Hom.: 453 Cov.: 32 AF XY: 0.0622 AC XY: 4620 AN XY: 74292

African (AFR) AF: 0.122 AC: 5052 AN: 41448

American (AMR) AF: 0.0443 AC: 676 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 490 AN: 3468

East Asian (EAS) AF: 0.0534 AC: 276 AN: 5170

South Asian (SAS) AF: 0.0621 AC: 299 AN: 4812

European-Finnish (FIN) AF: 0.00841 AC: 89 AN: 10584

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.0376 AC: 2556 AN: 67988

Other (OTH) AF: 0.0640 AC: 135 AN: 2108

Alfa AF: 0.0597 Hom.: 117

Bravo AF: 0.0682

Asia WGS AF: 0.0740 AC: 259 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.0
DANN	Benign	0.61
PhyloP100		-0.28
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: rs206801; hg19: chr2-31628746; COSMIC: COSV65147647;