2-31370399-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000379.4(XDH):c.1936A>G(p.Ile646Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.03 in 1,614,194 control chromosomes in the GnomAD database, including 856 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 58 hom., cov: 33)

Exomes 𝑓: 0.031 ( 798 hom. )

Consequence

XDH
NM_000379.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.77

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:

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=0.0021888316).

BP6

Variant 2-31370399-T-C is Benign according to our data. Variant chr2-31370399-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 335777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-31370399-T-C is described in Lovd as [Benign]. Variant chr2-31370399-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0227 (3460/152352) while in subpopulation NFE AF= 0.0307 (2091/68034). AF 95% confidence interval is 0.0296. There are 58 homozygotes in gnomad4. There are 1686 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XDH	NM_000379.4 link	c.1936A>G	p.Ile646Val	missense_variant	Exon 18 of 36	ENST00000379416.4	NP_000370.2	P47989
XDH	XM_011533095.3 link	c.1933A>G	p.Ile645Val	missense_variant	Exon 18 of 36		XP_011531397.1
XDH	XM_011533096.3 link	c.1936A>G	p.Ile646Val	missense_variant	Exon 18 of 29		XP_011531398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4 link	c.1936A>G	p.Ile646Val	missense_variant	Exon 18 of 36	1	NM_000379.4	ENSP00000368727.3		P47989

Frequencies

GnomAD3 genomes

AF:

0.0227

AC:

3460

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00630

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0251

Gnomad ASJ

AF:

0.0556

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0234

Gnomad FIN

AF:

0.0297

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0308

Gnomad OTH

AF:

0.0325

GnomAD3 exomes

AF:

0.0251

AC:

6322

AN:

251456

Hom.:

117

AF XY:

0.0266

AC XY:

3620

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00658

Gnomad AMR exome

AF:

0.0136

Gnomad ASJ exome

AF:

0.0479

Gnomad EAS exome

AF:

0.00174

Gnomad SAS exome

AF:

0.0282

Gnomad FIN exome

AF:

0.0316

Gnomad NFE exome

AF:

0.0310

Gnomad OTH exome

AF:

0.0256

GnomAD4 exome

AF:

0.0307

AC:

44919

AN:

1461842

Hom.:

798

Cov.:

AF XY:

0.0307

AC XY:

22327

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00556

Gnomad4 AMR exome

AF:

0.0140

Gnomad4 ASJ exome

AF:

0.0478

Gnomad4 EAS exome

AF:

0.000957

Gnomad4 SAS exome

AF:

0.0256

Gnomad4 FIN exome

AF:

0.0308

Gnomad4 NFE exome

AF:

0.0332

Gnomad4 OTH exome

AF:

0.0289

GnomAD4 genome

AF:

0.0227

AC:

3460

AN:

152352

Hom.:

Cov.:

AF XY:

0.0226

AC XY:

1686

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00628

Gnomad4 AMR

AF:

0.0250

Gnomad4 ASJ

AF:

0.0556

Gnomad4 EAS

AF:

0.00173

Gnomad4 SAS

AF:

0.0236

Gnomad4 FIN

AF:

0.0297

Gnomad4 NFE

AF:

0.0307

Gnomad4 OTH

AF:

0.0322

Alfa

AF:

0.0295

Hom.:

123

Bravo

AF:

0.0213

TwinsUK

AF:

0.0367

AC:

136

ALSPAC

AF:

0.0304

AC:

117

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0340

AC:

292

ExAC

AF:

0.0249

AC:

3026

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0334

EpiControl

AF:

0.0350

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

- -

May 29, 2024

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Xanthinuria type II

Benign:1

Jan 27, 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

0.063

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.012

DANN

Benign

0.28

DEOGEN2

Benign

0.013

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.72

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.050

REVEL

Benign

0.0080

Sift

Benign

0.53

Sift4G

Benign

0.52

Polyphen

0.0

Vest4

0.0070

MPC

0.033

ClinPred

0.00049

GERP RS

-9.7

Varity_R

0.070

gMVP

0.39

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

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