18-36187605-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017947.4(MOCOS):c.66C>A(p.Ser22Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0859 in 1,248,948 control chromosomes in the GnomAD database, including 5,035 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (438 hom., cov: 34)
  • Exomes 𝑓: 0.088 (4597 hom.)
• Consequence: MOCOS NM_017947.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.311

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015840232).
• BP6: Variant 18-36187605-C-A is Benign according to our data. Variant chr18-36187605-C-A is described in ClinVar as [Benign]. Clinvar id is 1168080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.093 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MOCOS	NM_017947.4	c.66C>A	p.Ser22Arg	missense_variant	1/15	ENST00000261326.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MOCOS	ENST00000261326.6	c.66C>A	p.Ser22Arg	missense_variant	1/15	1	NM_017947.4	P1

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10580 AN: 152176 Hom.: 438 Cov.: 34

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0681

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.00368

Gnomad SAS AF: 0.0337

Gnomad FIN AF: 0.0814

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0950

Gnomad OTH AF: 0.0979

GnomAD3 exomes AF: 0.0820 AC: 1434 AN: 17482 Hom.: 58 AF XY: 0.0864 AC XY: 845 AN XY: 9780

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.0453

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.00111

Gnomad SAS exome AF: 0.0323

Gnomad FIN exome AF: 0.0792

Gnomad NFE exome AF: 0.0963

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.0882 AC: 96716 AN: 1096662 Hom.: 4597 Cov.: 34 AF XY: 0.0889 AC XY: 46275 AN XY: 520404

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.0658

Gnomad4 ASJ exome AF: 0.162

Gnomad4 EAS exome AF: 0.000662

Gnomad4 SAS exome AF: 0.0348

Gnomad4 FIN exome AF: 0.0906

Gnomad4 NFE exome AF: 0.0927

Gnomad4 OTH exome AF: 0.0866

GnomAD4 genome AF: 0.0694 AC: 10569 AN: 152286 Hom.: 438 Cov.: 34 AF XY: 0.0680 AC XY: 5063 AN XY: 74448

Gnomad4 AFR AF: 0.0261

Gnomad4 AMR AF: 0.0680

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.00369

Gnomad4 SAS AF: 0.0337

Gnomad4 FIN AF: 0.0814

Gnomad4 NFE AF: 0.0950

Gnomad4 OTH AF: 0.0964

Alfa AF: 0.0595 Hom.: 70

Bravo AF: 0.0690

TwinsUK AF: 0.101 AC: 373

ALSPAC AF: 0.0942 AC: 363

ESP6500AA AF: 0.0219 AC: 76

ESP6500EA AF: 0.0771 AC: 538

ExAC AF: 0.0426 AC: 3974

Asia WGS AF: 0.0210 AC: 73 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Xanthinuria type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.034
Sift	Benign	0.056	T
Sift4G	Uncertain	0.013	D
Polyphen		0.97	D
Vest4		0.15
MutPred		0.31		Loss of phosphorylation at S22 (P = 0.0115);
MPC		2.5
ClinPred		0.022	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.10
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs113873219; hg19: chr18-33767568; COSMIC: COSV54340658; COSMIC: COSV54340658;