chr18-36187630-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_017947.4(MOCOS):c.91G>T(p.Gly31Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G31R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MOCOS
NM_017947.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.860

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28248435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOCOS	NM_017947.4 link	c.91G>T	p.Gly31Cys	missense_variant	Exon 1 of 15	ENST00000261326.6	NP_060417.4	Q96EN8
COSMOC	NR_134605.1 link	n.-195C>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MOCOS	ENST00000261326.6 link	c.91G>T	p.Gly31Cys	missense_variant	Exon 1 of 15	1	NM_017947.4	ENSP00000261326.4	Q96EN8
COSMOC	ENST00000568654.3 link	n.-156C>A		upstream_gene_variant		1
COSMOC	ENST00000687261.3 link	n.-155C>A		upstream_gene_variant
COSMOC	ENST00000738210.1 link	n.-210C>A		upstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1098054

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

521078

African (AFR)

AF:

0.00

AC:

AN:

23602

American (AMR)

AF:

0.00

AC:

AN:

9006

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14530

East Asian (EAS)

AF:

0.00

AC:

AN:

27328

South Asian (SAS)

AF:

0.00

AC:

AN:

23084

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3818

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

928978

Other (OTH)

AF:

0.00

AC:

AN:

44332

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Xanthinuria type II

Uncertain:1

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 31 of the MOCOS protein (p.Gly31Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MOCOS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1502809). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MOCOS protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.089

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.49

M_CAP

Benign

0.013

MetaRNN

Benign

0.28

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

0.86

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.083

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.013

Polyphen

0.99

Vest4

0.34

MutPred

0.49

Loss of disorder (P = 0.0143);

MVP

0.51

MPC

2.7

ClinPred

0.95

GERP RS

1.4

PromoterAI

-0.093

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.33

gMVP

0.48

Mutation Taster

=96/4

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over