rs104893969
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001358530.2(MOCS1):c.956G>A(p.Arg319Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,018 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 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
MOCS1
NM_001358530.2 missense
NM_001358530.2 missense
Scores
14
3
1
Clinical Significance
Conservation
PhyloP100: 7.86
Genes affected
MOCS1 (HGNC:7190): (molybdenum cofactor synthesis 1) Molybdenum cofactor biosynthesis is a conserved pathway leading to the biological activation of molybdenum. The protein encoded by this gene is involved in this pathway. This gene was originally thought to produce a bicistronic mRNA with the potential to produce two proteins (MOCS1A and MOCS1B) from adjacent open reading frames. However, only the first open reading frame (MOCS1A) has been found to encode a protein from the putative bicistronic mRNA, whereas additional splice variants are likely to produce a fusion between the two open reading frames. This gene is defective in patients with molybdenum cofactor deficiency, type A. A related pseudogene has been identified on chromosome 16. [provided by RefSeq, Nov 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.97
PP5
?
Variant 6-39912289-C-T is Pathogenic according to our data. Variant chr6-39912289-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MOCS1 | NM_001358530.2 | c.956G>A | p.Arg319Gln | missense_variant | 8/11 | ENST00000340692.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MOCS1 | ENST00000340692.10 | c.956G>A | p.Arg319Gln | missense_variant | 8/11 | 5 | NM_001358530.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152188Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251476Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135912
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GnomAD4 exome AF: 0.0000356 AC: 52AN: 1460830Hom.: 0 Cov.: 31 AF XY: 0.0000427 AC XY: 31AN XY: 726726
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 01, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1998 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 319 of the MOCS1 protein (p.Arg319Gln). This variant is present in population databases (rs104893969, gnomAD 0.02%). This missense change has been observed in individuals with molybdenum cofactor deficiency (PMID: 9921896, 35192225). ClinVar contains an entry for this variant (Variation ID: 6119). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
MOCS1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 24, 2023 | The MOCS1 c.956G>A variant is predicted to result in the amino acid substitution p.Arg319Gln. This variant has been reported in the homozygous and presumed compound heterozygous states in individuals with molybdenum cofactor deficiency (Reiss et al. 1998. PubMed ID: 9921896). In one study of MoCo-deficient patients, this variant was identified in 15% of the patients tested (Reiss et al. 1998. PubMed ID: 9921896). This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-39880033-C-T) and it reported as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6119/). This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;H
MutationTaster
Benign
A;A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;D
Vest4
MutPred
Loss of methylation at R317 (P = 0.0575);.;Loss of methylation at R317 (P = 0.0575);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at