NM_000379.4:c.1243-43A>G

Variant names:

• chr2-31377280-T-C
• rs10187719
• NM_000379.4:c.1243-43A>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.1243-43A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,611,930 control chromosomes in the GnomAD database, including 423,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41600 hom., cov: 31)
  • Exomes 𝑓: 0.72 (381935 hom.)
• Consequence: XDH NM_000379.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.129
• Publications: 6 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=-0.9).
• BP6: Variant 2-31377280-T-C is Benign according to our data. Variant chr2-31377280-T-C is described in ClinVar as Benign. ClinVar VariationId is 1249715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.776 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.1243-43A>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.1243-43A>G		intron	N/A	ENSP00000368727.3
	XDH	ENST00000879520.1		c.1351-43A>G		intron	N/A	ENSP00000549579.1
	XDH	ENST00000879524.1		c.1243-43A>G		intron	N/A	ENSP00000549583.1

Frequencies

GnomAD3 genomes AF: 0.739 AC: 112283 AN: 151948 Hom.: 41563 Cov.: 31

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.800

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.756

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.719

Gnomad OTH AF: 0.718

GnomAD2 exomes AF: 0.730 AC: 182454 AN: 249966 AF XY: 0.729

Gnomad AFR exome AF: 0.784

Gnomad AMR exome AF: 0.703

Gnomad ASJ exome AF: 0.770

Gnomad EAS exome AF: 0.754

Gnomad FIN exome AF: 0.730

Gnomad NFE exome AF: 0.721

Gnomad OTH exome AF: 0.707

GnomAD4 exome AF: 0.723 AC: 1055204 AN: 1459862 Hom.: 381935 Cov.: 36 AF XY: 0.723 AC XY: 524937 AN XY: 726318

African (AFR) AF: 0.782 AC: 26144 AN: 33448

American (AMR) AF: 0.702 AC: 31341 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 20107 AN: 26134

East Asian (EAS) AF: 0.770 AC: 30553 AN: 39680

South Asian (SAS) AF: 0.744 AC: 64107 AN: 86166

European-Finnish (FIN) AF: 0.723 AC: 38533 AN: 53286

Middle Eastern (MID) AF: 0.702 AC: 3409 AN: 4854

European-Non Finnish (NFE) AF: 0.718 AC: 797700 AN: 1111352

Other (OTH) AF: 0.719 AC: 43310 AN: 60276

GnomAD4 genome AF: 0.739 AC: 112365 AN: 152068 Hom.: 41600 Cov.: 31 AF XY: 0.739 AC XY: 54884 AN XY: 74316

African (AFR) AF: 0.783 AC: 32463 AN: 41466

American (AMR) AF: 0.702 AC: 10722 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2655 AN: 3468

East Asian (EAS) AF: 0.757 AC: 3896 AN: 5150

South Asian (SAS) AF: 0.730 AC: 3514 AN: 4814

European-Finnish (FIN) AF: 0.739 AC: 7821 AN: 10580

Middle Eastern (MID) AF: 0.623 AC: 182 AN: 292

European-Non Finnish (NFE) AF: 0.719 AC: 48874 AN: 67990

Other (OTH) AF: 0.713 AC: 1508 AN: 2114

Alfa AF: 0.714 Hom.: 10262

Bravo AF: 0.740

Asia WGS AF: 0.718 AC: 2497 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary xanthinuria type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.48
PhyloP100		-0.13
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: rs10187719; hg19: chr2-31600146;