rs397518419
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001358530.2(MOCS1):βc.1508_1509delβ(p.Glu503AlafsTer103) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 33)
Exomes π: 0.0000034 ( 0 hom. )
Consequence
MOCS1
NM_001358530.2 frameshift
NM_001358530.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.35
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.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.211 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-39906758-GCT-G is Pathogenic according to our data. Variant chr6-39906758-GCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MOCS1 | NM_001358530.2 | c.1508_1509del | p.Glu503AlafsTer103 | frameshift_variant | 11/11 | ENST00000340692.10 | NP_001345459.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MOCS1 | ENST00000340692.10 | c.1508_1509del | p.Glu503AlafsTer103 | frameshift_variant | 11/11 | 5 | NM_001358530.2 | ENSP00000344794 | P1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251360Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135892
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461870Hom.: 0 AF XY: 0.00000688 AC XY: 5AN XY: 727236
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GnomAD4 genome 0.00000656 AC: 1AN: 152340Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74492
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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:4
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Jan 01, 2019 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1998 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 06, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 09, 2023 | This sequence change creates a premature translational stop signal (p.Glu503Alafs*103) in the MOCS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 134 amino acid(s) of the MOCS1 protein. This variant is present in population databases (rs397518419, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with Molybdenum cofactor deficiency (PMID: 9731530, 9921896). This variant is also known as 1523delAG. ClinVar contains an entry for this variant (Variation ID: 6118). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at