chr18-36187579-AC-A

Variant names:

• chr18-36187579-AC-A
• rs2091346076
• NM_017947.4:c.42delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_017947.4(MOCOS):​c.42delC​(p.Phe15SerfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MOCOS NM_017947.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: -1.45
• Publications: 0 publications found

Genes affected

MOCOS (HGNC:18234): (molybdenum cofactor sulfurase) This gene encodes an enzyme that sulfurates the molybdenum cofactor which is required for activation of the xanthine dehydrogenase (XDH) and aldehyde oxidase (AO) enzymes. XDH catalyzes the conversion of hypoxanthine to uric acid via xanthine, as well as the conversion of allopurinol to oxypurinol, and pyrazinamide to 5-hydroxy pyrazinamide. Mutations in this gene cause the metabolic disorder classical xanthinuria type II which is characterized by the loss of XDH/XO and AO enzyme activity, decreased levels of uric acid in the urine, increased levels of xanthine and hypoxanthine in the serum and urine, formation of xanthine stones in the urinary tract, and myositis due to tissue deposition of xanthine. [provided by RefSeq, Apr 2017]

COSMOC (HGNC:51610): (cell fate and sterol metabolism associated divergent transcript of MOCOS)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 27 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-36187579-AC-A is Pathogenic according to our data. Variant chr18-36187579-AC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3008121.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017947.4. 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
	MOCOS	NM_017947.4	MANE Select	c.42delC	p.Phe15SerfsTer12	frameshift	Exon 1 of 15	NP_060417.4	Q96EN8
	COSMOC	NR_134605.1		n.-145delG		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MOCOS	ENST00000261326.6	TSL:1 MANE Select	c.42delC	p.Phe15SerfsTer12	frameshift	Exon 1 of 15	ENSP00000261326.4	Q96EN8
	MOCOS	ENST00000880903.1		c.42delC	p.Phe15SerfsTer12	frameshift	Exon 1 of 16	ENSP00000550962.1
	MOCOS	ENST00000880908.1		c.42delC	p.Phe15SerfsTer12	frameshift	Exon 1 of 14	ENSP00000550967.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Xanthinuria type II (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.4

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: rs2091346076; hg19: chr18-33767542;