2-31348920-A-C

Position:

• chr2-31348920-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000379.4(XDH):​c.3030T>G​(p.Phe1010Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F1010F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: XDH NM_000379.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XDH	NM_000379.4	c.3030T>G	p.Phe1010Leu	missense_variant	27/36	ENST00000379416.4	NP_000370.2
XDH	XM_011533095.3	c.3027T>G	p.Phe1009Leu	missense_variant	27/36		XP_011531397.1
XDH	XM_011533096.3	c.3030T>G	p.Phe1010Leu	missense_variant	27/29		XP_011531398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4	c.3030T>G	p.Phe1010Leu	missense_variant	27/36	1	NM_000379.4	ENSP00000368727.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.33
Sift	Benign	0.14	T
Sift4G	Benign	0.075	T
Polyphen		0.99	D
Vest4		0.82
MutPred		0.80		Loss of ubiquitination at K1005 (P = 0.1264);
MVP		0.61
MPC		0.26
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.90
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs1884725; hg19: chr2-31571786;