rs45612738

Positions:

• chr2-31379975-G-A

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.1134C>T​(p.Gly378=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,613,820 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (84 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (110 hom.)
• Consequence: XDH NM_000379.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003140
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0190

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 (BayesDel_noAF=-0.52).
• BP6: Variant 2-31379975-G-A is Benign according to our data. Variant chr2-31379975-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 335792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XDH	NM_000379.4	c.1134C>T	p.Gly378=	splice_region_variant, synonymous_variant	13/36	ENST00000379416.4
XDH	XM_011533095.3	c.1134C>T	p.Gly378=	splice_region_variant, synonymous_variant	13/36
XDH	XM_011533096.3	c.1134C>T	p.Gly378=	splice_region_variant, synonymous_variant	13/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XDH	ENST00000379416.4	c.1134C>T	p.Gly378=	splice_region_variant, synonymous_variant	13/36	1	NM_000379.4	P1

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2902 AN: 152174 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.0657

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

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: 0.000441

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00522 AC: 1313 AN: 251418 Hom.: 48 AF XY: 0.00365 AC XY: 496 AN XY: 135872

Gnomad AFR exome AF: 0.0679

Gnomad AMR exome AF: 0.00278

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: 0.000378

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00231 AC: 3371 AN: 1461528 Hom.: 110 Cov.: 31 AF XY: 0.00199 AC XY: 1445 AN XY: 727070

Gnomad4 AFR exome AF: 0.0723

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.00524

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000269

Gnomad4 OTH exome AF: 0.00553

GnomAD4 genome AF: 0.0191 AC: 2905 AN: 152292 Hom.: 84 Cov.: 32 AF XY: 0.0182 AC XY: 1357 AN XY: 74474

Gnomad4 AFR AF: 0.0656

Gnomad4 AMR AF: 0.00725

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00431 Hom.: 38

Bravo AF: 0.0227

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

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). 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. -

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
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.2
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0040
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: rs45612738; hg19: chr2-31602841;