2-31403179-G-C

Variant names:

• chr2-31403179-G-C
• rs1346644
• NM_000379.4:c.101-35C>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.101-35C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,609,170 control chromosomes in the GnomAD database, including 17,428 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1619 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15809 hom.)
• Consequence: XDH NM_000379.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.662
• Publications: 7 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=-0.66).
• BP6: Variant 2-31403179-G-C is Benign according to our data. Variant chr2-31403179-G-C is described in ClinVar as Benign. ClinVar VariationId is 1267257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000379.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	NM_000379.4	MANE Select	c.101-35C>G		intron	N/A	NP_000370.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	ENST00000379416.4	TSL:1 MANE Select	c.101-35C>G		intron	N/A	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20934 AN: 152134 Hom.: 1614 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0482

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.128 AC: 31835 AN: 249614 AF XY: 0.132

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0766

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.0483

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.144 AC: 209289 AN: 1456918 Hom.: 15809 Cov.: 29 AF XY: 0.144 AC XY: 104653 AN XY: 724916

African (AFR) AF: 0.145 AC: 4853 AN: 33404

American (AMR) AF: 0.0806 AC: 3605 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 3192 AN: 26102

East Asian (EAS) AF: 0.0671 AC: 2661 AN: 39632

South Asian (SAS) AF: 0.158 AC: 13590 AN: 86176

European-Finnish (FIN) AF: 0.123 AC: 6476 AN: 52658

Middle Eastern (MID) AF: 0.152 AC: 875 AN: 5758

European-Non Finnish (NFE) AF: 0.149 AC: 165406 AN: 1108258

Other (OTH) AF: 0.143 AC: 8631 AN: 60228

GnomAD4 genome AF: 0.138 AC: 20965 AN: 152252 Hom.: 1619 Cov.: 32 AF XY: 0.137 AC XY: 10229 AN XY: 74458

African (AFR) AF: 0.143 AC: 5935 AN: 41520

American (AMR) AF: 0.113 AC: 1726 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 436 AN: 3470

East Asian (EAS) AF: 0.0481 AC: 249 AN: 5172

South Asian (SAS) AF: 0.163 AC: 786 AN: 4830

European-Finnish (FIN) AF: 0.124 AC: 1312 AN: 10612

Middle Eastern (MID) AF: 0.185 AC: 54 AN: 292

European-Non Finnish (NFE) AF: 0.147 AC: 9998 AN: 68024

Other (OTH) AF: 0.150 AC: 317 AN: 2112

Alfa AF: 0.136 Hom.: 261

Bravo AF: 0.136

Asia WGS AF: 0.105 AC: 365 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

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.76
PhyloP100		0.66
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: rs1346644; hg19: chr2-31626045; COSMIC: COSV65151092;