rs1054889

Variant names:

• chr2-31334442-G-A
• rs1054889
• NM_000379.4:c.*1516C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-31334442-G-A
• chr2-31334442-G-C
• chr2-31334442-G-T

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.*1516C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 152,058 control chromosomes in the GnomAD database, including 14,475 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14475 hom., cov: 32)
  • Exomes 𝑓: 0.33 (0 hom.)
• Consequence: XDH NM_000379.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.18
• Publications: 11 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=-0.85).
• BP6: Variant 2-31334442-G-A is Benign according to our data. Variant chr2-31334442-G-A is described in ClinVar as Benign. ClinVar VariationId is 335734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XDH	NM_000379.4	c.*1516C>T		3_prime_UTR_variant	Exon 36 of 36	ENST00000379416.4	NP_000370.2
XDH	XM_011533095.3	c.*1516C>T		3_prime_UTR_variant	Exon 36 of 36		XP_011531397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XDH	ENST00000379416.4	c.*1516C>T		3_prime_UTR_variant	Exon 36 of 36	1	NM_000379.4	ENSP00000368727.3

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62162 AN: 151934 Hom.: 14478 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.538

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.404

GnomAD4 exome AF: 0.333 AC: 2 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 2 AN: 4

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.409 AC: 62173 AN: 152052 Hom.: 14475 Cov.: 32 AF XY: 0.418 AC XY: 31094 AN XY: 74314

African (AFR) AF: 0.178 AC: 7372 AN: 41510

American (AMR) AF: 0.538 AC: 8216 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1434 AN: 3468

East Asian (EAS) AF: 0.583 AC: 3008 AN: 5158

South Asian (SAS) AF: 0.470 AC: 2265 AN: 4822

European-Finnish (FIN) AF: 0.595 AC: 6275 AN: 10552

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32309 AN: 67954

Other (OTH) AF: 0.406 AC: 854 AN: 2104

Alfa AF: 0.444 Hom.: 47587

Bravo AF: 0.397

Asia WGS AF: 0.491 AC: 1707 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary xanthinuria type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.7
DANN	Benign	0.31
PhyloP100		2.2
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: rs1054889; hg19: chr2-31557308;