chr18-36260173-C-G

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.2407C>G(p.Gln803Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

MOCOS
NM_017947.4 missense, splice_region

Scores

Splicing: ADA: 0.009454

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.51

Publications

1 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 Gene-Disease associations (from GenCC):

xanthinuria type II
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

MOCOS 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=0.23094863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOCOS	NM_017947.4 link	c.2407C>G	p.Gln803Glu	missense_variant, splice_region_variant	Exon 13 of 15	ENST00000261326.6	NP_060417.4	Q96EN8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MOCOS	ENST00000261326.6 link	c.2407C>G	p.Gln803Glu	missense_variant, splice_region_variant	Exon 13 of 15	1	NM_017947.4	ENSP00000261326.4		Q96EN8
MOCOS	ENST00000588132.1 link	n.364C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251416

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111972

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xanthinuria type II

Uncertain:2

Sep 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine with glutamic acid at codon 803 of the MOCOS protein (p.Gln803Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MOCOS-related disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.017

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.080

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.81

M_CAP

Benign

0.0043

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.52

PhyloP100

2.5

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.98

REVEL

Benign

0.063

Sift

Benign

0.50

Sift4G

Benign

0.93

Polyphen

0.20

Vest4

0.43

MutPred

0.53

Loss of sheet (P = 0.0817);

MVP

0.31

MPC

0.10

ClinPred

0.49

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.50

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0095

dbscSNV1_RF

Benign

0.082

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over