rs397518418

Positions:

• chr6-39913351-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001358530.2(MOCS1):​c.722delT​(p.Leu241fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MOCS1 NM_001358530.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.28

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]

MOCS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-39913351-CA-C is Pathogenic according to our data. Variant chr6-39913351-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 6117.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MOCS1	NM_001358530.2	c.722delT	p.Leu241fs	frameshift_variant	6/11	ENST00000340692.10	NP_001345459.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MOCS1	ENST00000340692.10	c.722delT	p.Leu241fs	frameshift_variant	6/11	5	NM_001358530.2	ENSP00000344794.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 6 of 11). (P) 0252 - Variant is homozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. At least other 7 variants predicted to result in NMD have been reported pathogenic (PMID: 21031595; PMID: 27289259). (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals. At least two patients with Molybdenum cofactor deficiency A have been reported homozygous (PMID: 9731530; PMID: 27289259). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1205 - Variant is maternally and paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs397518418; hg19: chr6-39881095;