18-36260173-C-T

Variant names:

• chr18-36260173-C-T
• rs774534818
• NM_017947.4:c.2407C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP3

The NM_017947.4(MOCOS):​c.2407C>T​(p.Gln803*) variant causes a stop gained, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MOCOS NM_017947.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.51
• Publications: 1 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]

MOCOS Gene-Disease associations (from GenCC):

• xanthinuria type II

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

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

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.2407C>T	p.Gln803*	stop_gained splice_region	Exon 13 of 15	NP_060417.4	Q96EN8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MOCOS	ENST00000261326.6	TSL:1 MANE Select	c.2407C>T	p.Gln803*	stop_gained splice_region	Exon 13 of 15	ENSP00000261326.4	Q96EN8
	MOCOS	ENST00000880903.1		c.2461C>T	p.Gln821*	stop_gained splice_region	Exon 14 of 16	ENSP00000550962.1
	MOCOS	ENST00000880908.1		c.2317C>T	p.Gln773*	stop_gained splice_region	Exon 12 of 14	ENSP00000550967.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.77	D
PhyloP100		2.5
Vest4		0.37
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
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: rs774534818; hg19: chr18-33840136;