18-36260092-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_017947.4(MOCOS):​c.2326C>T​(p.Arg776Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

MOCOS
NM_017947.4 missense

Scores

11
5
3

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.10
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 18-36260092-C-T is Pathogenic according to our data. Variant chr18-36260092-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 253162.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MOCOSNM_017947.4 linkuse as main transcriptc.2326C>T p.Arg776Cys missense_variant 13/15 ENST00000261326.6 NP_060417.4 Q96EN8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MOCOSENST00000261326.6 linkuse as main transcriptc.2326C>T p.Arg776Cys missense_variant 13/151 NM_017947.4 ENSP00000261326.4 Q96EN8
MOCOSENST00000588132.1 linkuse as main transcriptn.283C>T non_coding_transcript_exon_variant 2/33

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251462
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000615
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000274
AC:
40
AN:
1461884
Hom.:
0
Cov.:
31
AF XY:
0.0000289
AC XY:
21
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000182
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.00
EpiControl
AF:
0.000237

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Xanthinuria type II Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 25, 2024- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 27, 2016- -
Likely pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterApr 04, 2024- -
Autism spectrum disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingGene Friend Way, National Innovation CenterJul 28, 2023Missense mutation in gene that has been shown to be linked to type II classical xanthinuria (PMID 17368066). Impaired expression of the MOCOS gene unit have been seen in ASD patient stem cells (PMID: 32327736). MOCOS polymorphism is associated with increased risk of autism spectrum disorder (PMID: 31900757). Altered MOCOS expression lead to abnormal neurodevelopment and neurotransmission, which associated with ASD (PMID: 26239292). In our study, two children diagnosed with autism spectrum disorder are carriers of this mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.39
T
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.035
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.19
D
MutationAssessor
Pathogenic
4.0
H
PrimateAI
Uncertain
0.50
T
PROVEAN
Pathogenic
-7.7
D
REVEL
Uncertain
0.58
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.95
MutPred
0.97
Loss of MoRF binding (P = 0.0405);
MVP
0.89
MPC
0.51
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.95
gMVP
0.88

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs750896617; hg19: chr18-33840055; COSMIC: COSV54341815; API