rs34929837

chr2-31379925-T-Achr2-31379925-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000379.4(XDH):c.1184A>T(p.Lys395Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 1,614,144 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (93 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (113 hom.)
• Consequence: XDH NM_000379.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.789

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006719202).
• BP6: Variant 2-31379925-T-A is Benign according to our data. Variant chr2-31379925-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 335791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-31379925-T-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XDH	NM_000379.4	c.1184A>T	p.Lys395Met	missense_variant	13/36	ENST00000379416.4
XDH	XM_011533095.3	c.1184A>T	p.Lys395Met	missense_variant	13/36
XDH	XM_011533096.3	c.1184A>T	p.Lys395Met	missense_variant	13/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XDH	ENST00000379416.4	c.1184A>T	p.Lys395Met	missense_variant	13/36	1	NM_000379.4	P1

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 3040 AN: 152190 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0687

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.00544 AC: 1367 AN: 251474 Hom.: 49 AF XY: 0.00383 AC XY: 520 AN XY: 135906

Gnomad AFR exome AF: 0.0704

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00238 AC: 3480 AN: 1461836 Hom.: 113 Cov.: 31 AF XY: 0.00205 AC XY: 1491 AN XY: 727222

Gnomad4 AFR exome AF: 0.0750

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00524

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000269

Gnomad4 OTH exome AF: 0.00573

GnomAD4 genome AF: 0.0200 AC: 3043 AN: 152308 Hom.: 93 Cov.: 32 AF XY: 0.0192 AC XY: 1428 AN XY: 74488

Gnomad4 AFR AF: 0.0686

Gnomad4 AMR AF: 0.00797

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00372 Hom.: 23

Bravo AF: 0.0237

ESP6500AA AF: 0.0660 AC: 291

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00648 AC: 787

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary xanthinuria type 1 Benign:2

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). 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2021

- -

Xanthinuria type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.97	D
Vest4		0.52
MVP		0.55
MPC		0.24
ClinPred		0.045	T
GERP RS		0.73
Varity_R		0.53
gMVP		0.76

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

Other links and lift over

dbSNP: rs34929837; hg19: chr2-31602791;