18-36187535-G-A

Variant names:

• chr18-36187535-G-A
• rs117090508
• NM_017947.4:c.-5G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017947.4(MOCOS):​c.-5G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0731 in 1,235,088 control chromosomes in the GnomAD database, including 3,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (327 hom., cov: 34)
  • Exomes 𝑓: 0.076 (3316 hom.)
• Consequence: MOCOS NM_017947.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.693
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 18-36187535-G-A is Benign according to our data. Variant chr18-36187535-G-A is described in ClinVar as [Benign]. Clinvar id is 1296803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOCOS	NM_017947.4	c.-5G>A		5_prime_UTR_variant	Exon 1 of 15	ENST00000261326.6	NP_060417.4
COSMOC	NR_134605.1	n.-100C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MOCOS	ENST00000261326.6	c.-5G>A		5_prime_UTR_variant	Exon 1 of 15	1	NM_017947.4	ENSP00000261326.4
COSMOC	ENST00000568654.3	n.-61C>T		upstream_gene_variant		1
COSMOC	ENST00000687261.3	n.-60C>T		upstream_gene_variant
COSMOC	ENST00000738210.1	n.-115C>T		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0537 AC: 8176 AN: 152138 Hom.: 327 Cov.: 34

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0445

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.0695

Gnomad FIN AF: 0.0578

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0732

Gnomad OTH AF: 0.0449

GnomAD2 exomes AF: 0.0761 AC: 673 AN: 8846 AF XY: 0.0761

Gnomad AFR exome AF: 0.00977

Gnomad AMR exome AF: 0.0437

Gnomad ASJ exome AF: 0.0522

Gnomad EAS exome AF: 0.197

Gnomad FIN exome AF: 0.0429

Gnomad NFE exome AF: 0.0844

Gnomad OTH exome AF: 0.0692

GnomAD4 exome AF: 0.0758 AC: 82093 AN: 1082838 Hom.: 3316 Cov.: 34 AF XY: 0.0758 AC XY: 38844 AN XY: 512262

African (AFR) AF: 0.0102 AC: 233 AN: 22952

American (AMR) AF: 0.0241 AC: 207 AN: 8586

Ashkenazi Jewish (ASJ) AF: 0.0434 AC: 619 AN: 14276

East Asian (EAS) AF: 0.141 AC: 3743 AN: 26562

South Asian (SAS) AF: 0.0657 AC: 1330 AN: 20256

European-Finnish (FIN) AF: 0.0598 AC: 1345 AN: 22496

Middle Eastern (MID) AF: 0.0591 AC: 175 AN: 2962

European-Non Finnish (NFE) AF: 0.0777 AC: 71546 AN: 921076

Other (OTH) AF: 0.0663 AC: 2895 AN: 43672

GnomAD4 genome AF: 0.0537 AC: 8173 AN: 152250 Hom.: 327 Cov.: 34 AF XY: 0.0535 AC XY: 3982 AN XY: 74430

African (AFR) AF: 0.0150 AC: 625 AN: 41566

American (AMR) AF: 0.0261 AC: 400 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0445 AC: 154 AN: 3464

East Asian (EAS) AF: 0.164 AC: 844 AN: 5142

South Asian (SAS) AF: 0.0695 AC: 336 AN: 4832

European-Finnish (FIN) AF: 0.0578 AC: 614 AN: 10614

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.0732 AC: 4980 AN: 68010

Other (OTH) AF: 0.0444 AC: 94 AN: 2116

Alfa AF: 0.0304 Hom.: 20

Bravo AF: 0.0509

Asia WGS AF: 0.0760 AC: 264 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MOCOS-related disorder Benign:1

Dec 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.6
DANN	Benign	0.77
PhyloP100		-0.69
PromoterAI		0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=299/1	polymorphism (auto)

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: rs117090508; hg19: chr18-33767498;