rs594445

chr18-36251226-C-Achr18-36251226-C-T

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.2107C>A(p.His703Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,613,574 control chromosomes in the GnomAD database, including 64,313 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.23 (4804 hom., cov: 32)
  • Exomes 𝑓: 0.28 (59509 hom.)
• Consequence: MOCOS NM_017947.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.58

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=0.0060777366).
• BP6: Variant 18-36251226-C-A is Benign according to our data. Variant chr18-36251226-C-A is described in ClinVar as [Benign]. Clinvar id is 1167883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MOCOS	NM_017947.4	c.2107C>A	p.His703Asn	missense_variant	11/15	ENST00000261326.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MOCOS	ENST00000261326.6	c.2107C>A	p.His703Asn	missense_variant	11/15	1	NM_017947.4	P1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35483 AN: 151942 Hom.: 4805 Cov.: 32

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.277

GnomAD3 exomes AF: 0.276 AC: 69332 AN: 251388 Hom.: 9954 AF XY: 0.278 AC XY: 37802 AN XY: 135858

Gnomad AFR exome AF: 0.0817

Gnomad AMR exome AF: 0.333

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.235

Gnomad SAS exome AF: 0.273

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.283

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.282 AC: 412499 AN: 1461514 Hom.: 59509 Cov.: 36 AF XY: 0.283 AC XY: 205531 AN XY: 727092

Gnomad4 AFR exome AF: 0.0865

Gnomad4 AMR exome AF: 0.329

Gnomad4 ASJ exome AF: 0.317

Gnomad4 EAS exome AF: 0.258

Gnomad4 SAS exome AF: 0.273

Gnomad4 FIN exome AF: 0.306

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome AF: 0.233 AC: 35487 AN: 152060 Hom.: 4804 Cov.: 32 AF XY: 0.239 AC XY: 17783 AN XY: 74306

Gnomad4 AFR AF: 0.0863

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.287

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.312

Gnomad4 NFE AF: 0.282

Gnomad4 OTH AF: 0.274

Alfa AF: 0.272 Hom.: 14588

Bravo AF: 0.230

TwinsUK AF: 0.284 AC: 1052

ALSPAC AF: 0.293 AC: 1128

ESP6500AA AF: 0.0919 AC: 405

ESP6500EA AF: 0.284 AC: 2442

ExAC AF: 0.269 AC: 32699

Asia WGS AF: 0.236 AC: 826 AN: 3478

EpiCase AF: 0.295

EpiControl AF: 0.290

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

This variant is associated with the following publications: (PMID: 27703193) -

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	0.10
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.045	T
Eigen	Benign	0.015
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.92	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.065
Sift	Benign	0.043	D
Sift4G	Benign	0.093	T
Polyphen		0.084	B
Vest4		0.10
MPC		0.12
ClinPred		0.028	T
GERP RS		5.5
Varity_R		0.43
gMVP		0.36

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: rs594445; hg19: chr18-33831189; COSMIC: COSV54341969;