NM_000379.4:c.514G>A

Variant names:

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.514G>A(p.Gly172Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,614,034 control chromosomes in the GnomAD database, including 805 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 64 hom., cov: 32)

Exomes 𝑓: 0.028 ( 741 hom. )

Consequence

XDH
NM_000379.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.75

Publications

21 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, Labcorp Genetics (formerly Invitae), Ambry Genetics

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=0.0027283728).

BP6

Variant 2-31388277-C-T is Benign according to our data. Variant chr2-31388277-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 335799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XDH	NM_000379.4 link	c.514G>A	p.Gly172Arg	missense_variant	Exon 7 of 36	ENST00000379416.4	NP_000370.2	P47989
XDH	XM_011533095.3 link	c.514G>A	p.Gly172Arg	missense_variant	Exon 7 of 36		XP_011531397.1
XDH	XM_011533096.3 link	c.514G>A	p.Gly172Arg	missense_variant	Exon 7 of 29		XP_011531398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4 link	c.514G>A	p.Gly172Arg	missense_variant	Exon 7 of 36	1	NM_000379.4	ENSP00000368727.3		P47989
XDH	ENST00000491727.5 link	n.57G>A		non_coding_transcript_exon_variant	Exon 2 of 6	3

Frequencies

GnomAD3 genomes

AF:

0.0252

AC:

3838

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0185

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0223

Gnomad ASJ

AF:

0.0421

Gnomad EAS

AF:

0.0441

Gnomad SAS

AF:

0.0563

Gnomad FIN

AF:

0.0116

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0275

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.0287

AC:

7219

AN:

251434

AF XY:

0.0312

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.0160

Gnomad ASJ exome

AF:

0.0358

Gnomad EAS exome

AF:

0.0458

Gnomad FIN exome

AF:

0.00970

Gnomad NFE exome

AF:

0.0270

Gnomad OTH exome

AF:

0.0290

GnomAD4 exome

AF:

0.0280

AC:

40905

AN:

1461756

Hom.:

741

Cov.:

AF XY:

0.0288

AC XY:

20959

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.0188

AC:

631

AN:

33480

American (AMR)

AF:

0.0167

AC:

746

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0332

AC:

868

AN:

26134

East Asian (EAS)

AF:

0.0604

AC:

2396

AN:

39700

South Asian (SAS)

AF:

0.0544

AC:

4695

AN:

86248

European-Finnish (FIN)

AF:

0.0112

AC:

596

AN:

53410

Middle Eastern (MID)

AF:

0.0421

AC:

243

AN:

5768

European-Non Finnish (NFE)

AF:

0.0259

AC:

28842

AN:

1111904

Other (OTH)

AF:

0.0313

AC:

1888

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

2179

4359

6538

8718

10897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1122

2244

3366

4488

5610

<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:

0.0252

AC:

3838

AN:

152278

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1885

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0185

AC:

768

AN:

41554

American (AMR)

AF:

0.0223

AC:

341

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0421

AC:

146

AN:

3470

East Asian (EAS)

AF:

0.0440

AC:

227

AN:

5162

South Asian (SAS)

AF:

0.0568

AC:

274

AN:

4828

European-Finnish (FIN)

AF:

0.0116

AC:

123

AN:

10616

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0275

AC:

1870

AN:

68024

Other (OTH)

AF:

0.0241

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

192

385

577

770

962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0265

Hom.:

235

Bravo

AF:

0.0241

TwinsUK

AF:

0.0240

AC:

ALSPAC

AF:

0.0234

AC:

ESP6500AA

AF:

0.0168

AC:

ESP6500EA

AF:

0.0260

AC:

224

ExAC

AF:

0.0295

AC:

3580

Asia WGS

AF:

0.0380

AC:

130

AN:

3478

EpiCase

AF:

0.0298

EpiControl

AF:

0.0340

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 11, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27703193, 27884173, 18712049, 20981092) -

Hereditary xanthinuria type 1

Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Xanthinuria type II

Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.047

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

PhyloP100

1.7

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.26

Sift

Benign

0.17

Sift4G

Benign

0.14

Polyphen

0.021

Vest4

0.13

MutPred

0.17

Loss of catalytic residue at G172 (P = 0.1212);

MPC

0.047

ClinPred

0.022

GERP RS

5.4

Varity_R

0.22

gMVP

0.65

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over