NM_000379.4:c.3736C>T

Variant names:

• chr2-31339527-G-A
• rs142329784
• NM_000379.4:c.3736C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000379.4(XDH):​c.3736C>T​(p.Arg1246Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000703 in 1,614,086 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1246H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (1 hom.)
• Consequence: XDH NM_000379.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.51
• Publications: 9 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 0 ACMG points.

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.3736C>T	p.Arg1246Cys	missense	Exon 34 of 36	NP_000370.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	ENST00000379416.4	TSL:1 MANE Select	c.3736C>T	p.Arg1246Cys	missense	Exon 34 of 36	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000406 AC: 102 AN: 251482 AF XY: 0.000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000853

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000731 AC: 1069 AN: 1461884 Hom.: 1 Cov.: 32 AF XY: 0.000689 AC XY: 501 AN XY: 727244

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5758

European-Non Finnish (NFE) AF: 0.000930 AC: 1034 AN: 1112012

Other (OTH) AF: 0.000265 AC: 16 AN: 60396

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74354

African (AFR) AF: 0.000169 AC: 7 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000867 AC: 59 AN: 68054

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000519 Hom.: 0

Bravo AF: 0.000363

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000453 AC: 55

EpiCase AF: 0.000436

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.099	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.31
Sift	Benign	0.035	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.87
MVP		0.87
MPC		0.29
ClinPred		0.52	D
GERP RS		5.0
Varity_R		0.43
gMVP		0.78
Mutation Taster		=70/30	polymorphism

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: rs142329784; hg19: chr2-31562393; COSMIC: COSV65147303;