rs17011368

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000379.4(XDH):c.2107A>G(p.Ile703Val) variant causes a missense change. The variant allele was found at a frequency of 0.0364 in 1,613,932 control chromosomes in the GnomAD database, including 1,453 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I703K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.055 ( 322 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1131 hom. )

Consequence

XDH
NM_000379.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.64

Publications

23 publications found

Variant links:

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)

XDH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027359426).

BP6

Variant 2-31368051-T-C is Benign according to our data. Variant chr2-31368051-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 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.2107A>G	p.Ile703Val	missense	Exon 20 of 36	NP_000370.2	P47989

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XDH	ENST00000379416.4	TSL:1 MANE Select	c.2107A>G	p.Ile703Val	missense	Exon 20 of 36	ENSP00000368727.3	P47989
XDH	ENST00000879520.1		c.2215A>G	p.Ile739Val	missense	Exon 20 of 36	ENSP00000549579.1
XDH	ENST00000879524.1		c.2116A>G	p.Ile706Val	missense	Exon 20 of 36	ENSP00000549583.1

Frequencies

GnomAD3 genomes

AF:

0.0547

AC:

8320

AN:

152172

Hom.:

322

Cov.:

show subpopulations

Gnomad AFR

AF:

0.115

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.0405

Gnomad ASJ

AF:

0.0605

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0297

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0317

Gnomad OTH

AF:

0.0602

GnomAD2 exomes

AF:

0.0338

AC:

8510

AN:

251456

AF XY:

0.0331

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.0205

Gnomad ASJ exome

AF:

0.0517

Gnomad EAS exome

AF:

0.00174

Gnomad FIN exome

AF:

0.0316

Gnomad NFE exome

AF:

0.0320

Gnomad OTH exome

AF:

0.0309

GnomAD4 exome

AF:

0.0345

AC:

50423

AN:

1461642

Hom.:

1131

Cov.:

AF XY:

0.0340

AC XY:

24744

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.119

AC:

3987

AN:

33474

American (AMR)

AF:

0.0215

AC:

963

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0516

AC:

1348

AN:

26130

East Asian (EAS)

AF:

0.000982

AC:

AN:

39698

South Asian (SAS)

AF:

0.0258

AC:

2224

AN:

86258

European-Finnish (FIN)

AF:

0.0308

AC:

1643

AN:

53412

Middle Eastern (MID)

AF:

0.0524

AC:

302

AN:

5768

European-Non Finnish (NFE)

AF:

0.0339

AC:

37678

AN:

1111790

Other (OTH)

AF:

0.0371

AC:

2239

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2482

4965

7447

9930

12412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1516

3032

4548

6064

7580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0547

AC:

8336

AN:

152290

Hom.:

322

Cov.:

AF XY:

0.0534

AC XY:

3976

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.115

AC:

4761

AN:

41544

American (AMR)

AF:

0.0404

AC:

618

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0605

AC:

210

AN:

3470

East Asian (EAS)

AF:

0.00174

AC:

AN:

5186

South Asian (SAS)

AF:

0.0238

AC:

115

AN:

4830

European-Finnish (FIN)

AF:

0.0297

AC:

315

AN:

10614

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0316

AC:

2152

AN:

68034

Other (OTH)

AF:

0.0596

AC:

126

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

383

766

1150

1533

1916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0379

Hom.:

723

Bravo

AF:

0.0569

TwinsUK

AF:

0.0369

AC:

137

ALSPAC

AF:

0.0309

AC:

119

ESP6500AA

AF:

0.115

AC:

508

ESP6500EA

AF:

0.0342

AC:

294

ExAC

AF:

0.0351

AC:

4257

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.0350

EpiControl

AF:

0.0366

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary xanthinuria type 1 (2)

not provided (2)

not specified (1)

Xanthinuria type II (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.061

Eigen

Benign

0.076

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

3.6

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.95

REVEL

Benign

0.073

Sift

Uncertain

0.016

Sift4G

Uncertain

0.058

Polyphen

0.013

Vest4

0.058

MPC

0.044

ClinPred

0.017

GERP RS

4.8

Varity_R

0.29

gMVP

0.61

Mutation Taster

=73/27

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over