chr18-36187544-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017947.4(MOCOS):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,084,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

MOCOS
NM_017947.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99

Publications

0 publications found

Variant links:

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 links:

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

COSMOC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19092888).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOCOS	NM_017947.4 link	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 15	ENST00000261326.6	NP_060417.4	Q96EN8
COSMOC	NR_134605.1 link	n.-109G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MOCOS	ENST00000261326.6 link	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 15	1	NM_017947.4	ENSP00000261326.4	Q96EN8
COSMOC	ENST00000568654.3 link	n.-70G>A		upstream_gene_variant		1
COSMOC	ENST00000687261.3 link	n.-69G>A		upstream_gene_variant
COSMOC	ENST00000738210.1 link	n.-124G>A		upstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000896

AC:

AN:

11162

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00179

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1084904

Hom.:

Cov.:

AF XY:

0.00000195

AC XY:

AN XY:

513492

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23052

American (AMR)

AF:

0.00

AC:

AN:

8726

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14308

East Asian (EAS)

AF:

0.0000375

AC:

AN:

26696

South Asian (SAS)

AF:

0.00

AC:

AN:

20466

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3006

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

922172

Other (OTH)

AF:

0.0000228

AC:

AN:

43772

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.044843), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 11, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5C>T (p.A2V) alteration is located in exon 1 (coding exon 1) of the MOCOS gene. This alteration results from a C to T substitution at nucleotide position 5, causing the alanine (A) at amino acid position 2 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

Eigen

Benign

-0.0011

Eigen_PC

Benign

-0.052

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.42

M_CAP

Benign

0.060

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

2.0

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.75

REVEL

Benign

0.085

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.29

MutPred

0.29

Loss of relative solvent accessibility (P = 0.0676);

MVP

0.41

MPC

2.1

ClinPred

0.25

GERP RS

3.2

PromoterAI

-0.22

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.20

gMVP

0.45

Mutation Taster

=95/5

polymorphism

(source)

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

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chr18-36187544-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over