rs1429374

Variant names:

• chr2-31349532-A-G
• rs1429374
• NM_000379.4:c.2969+154T>C

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.2969+154T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 152,014 control chromosomes in the GnomAD database, including 28,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.59 (28793 hom., cov: 32)
• Consequence: XDH NM_000379.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.362
• Publications: 3 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 (BayesDel_noAF=-0.85).
• BP6: Variant 2-31349532-A-G is Benign according to our data. Variant chr2-31349532-A-G is described in ClinVar as Benign. ClinVar VariationId is 1249198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XDH	NM_000379.4	c.2969+154T>C		intron_variant	Intron 26 of 35	ENST00000379416.4	NP_000370.2
XDH	XM_011533095.3	c.2966+154T>C		intron_variant	Intron 26 of 35		XP_011531397.1
XDH	XM_011533096.3	c.2969+154T>C		intron_variant	Intron 26 of 28		XP_011531398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4	c.2969+154T>C		intron_variant	Intron 26 of 35	1	NM_000379.4	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.594 AC: 90251 AN: 151896 Hom.: 28805 Cov.: 32

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.836

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.713

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.612

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.594 AC: 90254 AN: 152014 Hom.: 28793 Cov.: 32 AF XY: 0.597 AC XY: 44363 AN XY: 74288

African (AFR) AF: 0.332 AC: 13749 AN: 41462

American (AMR) AF: 0.634 AC: 9684 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 2474 AN: 3470

East Asian (EAS) AF: 0.773 AC: 3980 AN: 5150

South Asian (SAS) AF: 0.721 AC: 3476 AN: 4818

European-Finnish (FIN) AF: 0.707 AC: 7462 AN: 10556

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.695 AC: 47218 AN: 67956

Other (OTH) AF: 0.609 AC: 1284 AN: 2110

Alfa AF: 0.636 Hom.: 3999

Bravo AF: 0.579

Asia WGS AF: 0.676 AC: 2349 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.6
DANN	Benign	0.48
PhyloP100		-0.36
Mutation Taster		=100/0	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: rs1429374; hg19: chr2-31572398;