rs45612738

Variant names:

• chr2-31379975-G-A
• rs45612738
• NM_000379.4:c.1134C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-31379975-G-A
• chr2-31379975-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.1134C>T​(p.Gly378Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,613,820 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (84 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (110 hom.)
• Consequence: XDH NM_000379.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003140
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0190
• Publications: 4 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-31379975-G-A is Benign according to our data. Variant chr2-31379975-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 335792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0635 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	NM_000379.4	MANE Select	c.1134C>T	p.Gly378Gly	splice_region synonymous	Exon 13 of 36	NP_000370.2	P47989

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XDH	ENST00000379416.4	TSL:1 MANE Select	c.1134C>T	p.Gly378Gly	splice_region synonymous	Exon 13 of 36	ENSP00000368727.3	P47989
	XDH	ENST00000879520.1		c.1242C>T	p.Gly414Gly	splice_region synonymous	Exon 13 of 36	ENSP00000549579.1
	XDH	ENST00000879524.1		c.1134C>T	p.Gly378Gly	splice_region synonymous	Exon 13 of 36	ENSP00000549583.1

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2902 AN: 152174 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.0657

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00522 AC: 1313 AN: 251418 AF XY: 0.00365

Gnomad AFR exome AF: 0.0679

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00231 AC: 3371 AN: 1461528 Hom.: 110 Cov.: 31 AF XY: 0.00199 AC XY: 1445 AN XY: 727070

African (AFR) AF: 0.0723 AC: 2417 AN: 33428

American (AMR) AF: 0.00313 AC: 140 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00524 AC: 137 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00359 AC: 20 AN: 5570

European-Non Finnish (NFE) AF: 0.000269 AC: 299 AN: 1111954

Other (OTH) AF: 0.00553 AC: 334 AN: 60360

GnomAD4 genome AF: 0.0191 AC: 2905 AN: 152292 Hom.: 84 Cov.: 32 AF XY: 0.0182 AC XY: 1357 AN XY: 74474

African (AFR) AF: 0.0656 AC: 2725 AN: 41550

American (AMR) AF: 0.00725 AC: 111 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68036

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00784 Hom.: 85

Bravo AF: 0.0227

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.2
DANN	Benign	0.66
PhyloP100		0.019
Mutation Taster		=75/25	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0040
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: rs45612738; hg19: chr2-31602841;