2-31344766-T-G

Variant names:

• chr2-31344766-T-G
• rs207454
• NM_000379.4:c.3352-30A>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.3352-30A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,612,780 control chromosomes in the GnomAD database, including 11,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.16 (2920 hom., cov: 32)
  • Exomes 𝑓: 0.098 (8303 hom.)
• Consequence: XDH NM_000379.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.583
• Publications: 11 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-31344766-T-G is Benign according to our data. Variant chr2-31344766-T-G is described in ClinVar as [Benign]. Clinvar id is 1234846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XDH	NM_000379.4	c.3352-30A>C		intron_variant	Intron 30 of 35	ENST00000379416.4	NP_000370.2
XDH	XM_011533095.3	c.3349-30A>C		intron_variant	Intron 30 of 35		XP_011531397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4	c.3352-30A>C		intron_variant	Intron 30 of 35	1	NM_000379.4	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24236 AN: 151980 Hom.: 2912 Cov.: 32

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0695

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0857

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.115 AC: 28593 AN: 249104 AF XY: 0.111

Gnomad AFR exome AF: 0.337

Gnomad AMR exome AF: 0.0851

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.157

Gnomad FIN exome AF: 0.0744

Gnomad NFE exome AF: 0.0876

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.0975 AC: 142456 AN: 1460682 Hom.: 8303 Cov.: 32 AF XY: 0.0975 AC XY: 70842 AN XY: 726612

African (AFR) AF: 0.334 AC: 11164 AN: 33472

American (AMR) AF: 0.0862 AC: 3842 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3595 AN: 26108

East Asian (EAS) AF: 0.154 AC: 6115 AN: 39664

South Asian (SAS) AF: 0.126 AC: 10817 AN: 86050

European-Finnish (FIN) AF: 0.0757 AC: 4031 AN: 53242

Middle Eastern (MID) AF: 0.113 AC: 649 AN: 5752

European-Non Finnish (NFE) AF: 0.0858 AC: 95405 AN: 1111494

Other (OTH) AF: 0.113 AC: 6838 AN: 60344

GnomAD4 genome AF: 0.160 AC: 24266 AN: 152098 Hom.: 2920 Cov.: 32 AF XY: 0.157 AC XY: 11646 AN XY: 74358

African (AFR) AF: 0.330 AC: 13703 AN: 41462

American (AMR) AF: 0.109 AC: 1660 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 452 AN: 3468

East Asian (EAS) AF: 0.156 AC: 800 AN: 5144

South Asian (SAS) AF: 0.133 AC: 643 AN: 4826

European-Finnish (FIN) AF: 0.0695 AC: 736 AN: 10594

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0857 AC: 5826 AN: 67996

Other (OTH) AF: 0.141 AC: 298 AN: 2112

Alfa AF: 0.118 Hom.: 2581

Bravo AF: 0.170

Asia WGS AF: 0.146 AC: 508 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.1
DANN	Benign	0.81
PhyloP100		-0.58
BranchPoint Hunter		3.0
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: rs207454; hg19: chr2-31567632; COSMIC: COSV65151082;