rs17011368

Variant names:

• chr2-31368051-T-C
• rs17011368
• NM_000379.4:c.2107A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-31368051-T-C
• chr2-31368051-T-G

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.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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.64
• Publications: 23 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 (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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XDH	NM_000379.4	c.2107A>G	p.Ile703Val	missense_variant	Exon 20 of 36	ENST00000379416.4	NP_000370.2
XDH	XM_011533095.3	c.2104A>G	p.Ile702Val	missense_variant	Exon 20 of 36		XP_011531397.1
XDH	XM_011533096.3	c.2107A>G	p.Ile703Val	missense_variant	Exon 20 of 29		XP_011531398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4	c.2107A>G	p.Ile703Val	missense_variant	Exon 20 of 36	1	NM_000379.4	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.0547 AC: 8320 AN: 152172 Hom.: 322 Cov.: 32

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

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.: 32 AF XY: 0.0340 AC XY: 24744 AN XY: 727136

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: 39 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

GnomAD4 genome AF: 0.0547 AC: 8336 AN: 152290 Hom.: 322 Cov.: 32 AF XY: 0.0534 AC XY: 3976 AN XY: 74484

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: 9 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: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0316 AC: 2152 AN: 68034

Other (OTH) AF: 0.0596 AC: 126 AN: 2114

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: 89 AN: 3478

EpiCase AF: 0.0350

EpiControl AF: 0.0366

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

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

This variant is associated with the following publications: (PMID: 27703193, 18300946)

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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.

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Xanthinuria type II Benign:1

Jan 31, 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	0.078
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T
Eigen	Benign	0.076
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.073
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.058	T
Vest4		0.058
ClinPred		0.017	T
GERP RS		4.8
Varity_R		0.29
gMVP		0.61
Mutation Taster		=73/27	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: rs17011368; hg19: chr2-31590917; COSMIC: COSV65149452;