rs45523133

Positions:

chr2-31388277-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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

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 links:

XDH (HGNC:):

XDH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 335799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-31388277-C-T is described in Lovd as [Benign]. Variant chr2-31388277-C-T is described in Lovd as [Likely_benign].

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/exons	MANE	Protein	UniProt
XDH	NM_000379.4 linkuse as main transcript	c.514G>A	p.Gly172Arg	missense_variant	7/36	ENST00000379416.4	NP_000370.2	P47989
XDH	XM_011533095.3 linkuse as main transcript	c.514G>A	p.Gly172Arg	missense_variant	7/36		XP_011531397.1
XDH	XM_011533096.3 linkuse as main transcript	c.514G>A	p.Gly172Arg	missense_variant	7/29		XP_011531398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4 linkuse as main transcript	c.514G>A	p.Gly172Arg	missense_variant	7/36	1	NM_000379.4	ENSP00000368727.3		P47989
XDH	ENST00000491727.5 linkuse as main transcript	n.57G>A		non_coding_transcript_exon_variant	2/6	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

GnomAD3 exomes

AF:

0.0287

AC:

7219

AN:

251434

Hom.:

157

AF XY:

0.0312

AC XY:

4246

AN XY:

135886

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 SAS exome

AF:

0.0560

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

Gnomad4 AFR exome

AF:

0.0188

Gnomad4 AMR exome

AF:

0.0167

Gnomad4 ASJ exome

AF:

0.0332

Gnomad4 EAS exome

AF:

0.0604

Gnomad4 SAS exome

AF:

0.0544

Gnomad4 FIN exome

AF:

0.0112

Gnomad4 NFE exome

AF:

0.0259

Gnomad4 OTH exome

AF:

0.0313

GnomAD4 genome

AF:

0.0252

AC:

3838

AN:

152278

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1885

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0185

Gnomad4 AMR

AF:

0.0223

Gnomad4 ASJ

AF:

0.0421

Gnomad4 EAS

AF:

0.0440

Gnomad4 SAS

AF:

0.0568

Gnomad4 FIN

AF:

0.0116

Gnomad4 NFE

AF:

0.0275

Gnomad4 OTH

AF:

0.0241

Alfa

AF:

0.0264

Hom.:

125

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2020	This variant is associated with the following publications: (PMID: 27703193, 27884173, 18712049, 20981092) -

Hereditary xanthinuria type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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

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

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

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over