rs148412639

Variant names:

• chr2-31373872-C-G
• rs148412639
• NM_000379.4:c.1686+1G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-31373872-C-G
• chr2-31373872-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PVS1_Moderate PP5 BS1_Supporting

The NM_000379.4(XDH):​c.1686+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000925 in 1,613,748 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (1 hom.)
• Consequence: XDH NM_000379.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 5.68
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.020989506 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8, offset of 9, new splice context is: acgGTcagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 2-31373872-C-G is Pathogenic according to our data. Variant chr2-31373872-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505602.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000962 (1406/1461464) while in subpopulation NFE AF = 0.00118 (1311/1111742). AF 95% confidence interval is 0.00113. There are 1 homozygotes in GnomAdExome4. There are 655 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	NM_000379.4	MANE Select	c.1686+1G>C		splice_donor intron	N/A	NP_000370.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	ENST00000379416.4	TSL:1 MANE Select	c.1686+1G>C		splice_donor intron	N/A	ENSP00000368727.3
	XDH	ENST00000879524.1		c.1687G>C	p.Val563Leu	missense	Exon 16 of 36	ENSP00000549583.1
	XDH	ENST00000879520.1		c.1794+1G>C		splice_donor intron	N/A	ENSP00000549579.1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000466 AC: 117 AN: 251112 AF XY: 0.000472

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000916

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000962 AC: 1406 AN: 1461464 Hom.: 1 Cov.: 31 AF XY: 0.000901 AC XY: 655 AN XY: 727036

African (AFR) AF: 0.000299 AC: 10 AN: 33466

American (AMR) AF: 0.000134 AC: 6 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53392

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00118 AC: 1311 AN: 1111742

Other (OTH) AF: 0.000977 AC: 59 AN: 60372

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74448

African (AFR) AF: 0.000120 AC: 5 AN: 41566

American (AMR) AF: 0.000262 AC: 4 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000750 Hom.: 0

Bravo AF: 0.000612

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.000927

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	Hereditary xanthinuria type 1 (5)
-	1	-	not provided (1)
1	-	-	Xanthinuria type II (1)
1	-	-	XDH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.7
GERP RS		5.8
Mutation Taster		=62/38	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
Splicevardb		2.0
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.52		Position offset: -3
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs148412639; hg19: chr2-31596738;