2-31398732-T-C

Variant names:

• chr2-31398732-T-C
• rs10175754
• NM_000379.4:c.307-33A>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.307-33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,612,096 control chromosomes in the GnomAD database, including 19,049 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1828 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17221 hom.)
• Consequence: XDH NM_000379.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.396
• Publications: 5 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=-0.82).
• BP6: Variant 2-31398732-T-C is Benign according to our data. Variant chr2-31398732-T-C is described in ClinVar as Benign. ClinVar VariationId is 1227980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 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.307-33A>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.307-33A>G		intron	N/A	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22564 AN: 151964 Hom.: 1831 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.151

GnomAD2 exomes AF: 0.130 AC: 32439 AN: 249752 AF XY: 0.133

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.0757

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.000925

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.148 AC: 216741 AN: 1460014 Hom.: 17221 Cov.: 32 AF XY: 0.149 AC XY: 108260 AN XY: 726288

African (AFR) AF: 0.182 AC: 6073 AN: 33442

American (AMR) AF: 0.0792 AC: 3539 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4695 AN: 26078

East Asian (EAS) AF: 0.000454 AC: 18 AN: 39644

South Asian (SAS) AF: 0.147 AC: 12652 AN: 86158

European-Finnish (FIN) AF: 0.126 AC: 6714 AN: 53168

Middle Eastern (MID) AF: 0.185 AC: 1052 AN: 5680

European-Non Finnish (NFE) AF: 0.156 AC: 173074 AN: 1110894

Other (OTH) AF: 0.148 AC: 8924 AN: 60254

GnomAD4 genome AF: 0.148 AC: 22574 AN: 152082 Hom.: 1828 Cov.: 32 AF XY: 0.145 AC XY: 10803 AN XY: 74330

African (AFR) AF: 0.180 AC: 7454 AN: 41494

American (AMR) AF: 0.113 AC: 1724 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 579 AN: 3470

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5170

South Asian (SAS) AF: 0.144 AC: 693 AN: 4816

European-Finnish (FIN) AF: 0.125 AC: 1329 AN: 10612

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10272 AN: 67994

Other (OTH) AF: 0.153 AC: 322 AN: 2106

Alfa AF: 0.146 Hom.: 2716

Bravo AF: 0.149

Asia WGS AF: 0.0910 AC: 316 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.8
DANN	Benign	0.28
PhyloP100		0.40
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: rs10175754; hg19: chr2-31621598;