rs398122797

Variant names:

• chr5-53098628-CTT-C
• rs398122797
• NM_004531.5:c.539_540delAA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_004531.5(MOCS2):​c.539_540delAA​(p.Lys180ArgfsTer31) variant causes a frameshift change. The variant allele was found at a frequency of 0.000107 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MOCS2 NM_004531.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.69

Genes affected

MOCS2 (HGNC:7193): (molybdenum cofactor synthesis 2) Eukaryotic molybdoenzymes use a unique molybdenum cofactor (MoCo) consisting of a pterin, termed molybdopterin, and the catalytically active metal molybdenum. MoCo is synthesized from precursor Z by the heterodimeric enzyme molybdopterin synthase. The large and small subunits of molybdopterin synthase are both encoded from this gene by overlapping open reading frames. The proteins were initially thought to be encoded from a bicistronic transcript. They are now thought to be encoded from monocistronic transcripts. Alternatively spliced transcripts have been found for this locus that encode the large and small subunits. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 0.0494 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-53098628-CTT-C is Pathogenic according to our data. Variant chr5-53098628-CTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53098628-CTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOCS2	NM_004531.5	c.539_540delAA	p.Lys180ArgfsTer31	frameshift_variant	Exon 7 of 7	ENST00000396954.8	NP_004522.1
MOCS2	NM_176806.4	c.*459_*460delAA		3_prime_UTR_variant	Exon 7 of 7	ENST00000450852.8	NP_789776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MOCS2	ENST00000396954.8	c.539_540delAA	p.Lys180ArgfsTer31	frameshift_variant	Exon 7 of 7	1	NM_004531.5	ENSP00000380157.3
MOCS2	ENST00000450852	c.*459_*460delAA		3_prime_UTR_variant	Exon 7 of 7	1	NM_176806.4	ENSP00000411022.3

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000162

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 251092 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135746

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000106 AC: 155 AN: 1461570 Hom.: 0 AF XY: 0.000103 AC XY: 75 AN XY: 727112

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74370

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000756

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B Pathogenic:3

Dec 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys180ArgfsX31 variant in MOCS2 has been reported in 4 individuals with clinical features of molybdenum cofactor deficiency (Reiss 1999). Three of these individuals were homozygous for this variant and one individual was compound heterozygous. This variant has also been identified in 0.01% (5/67564) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs398122797). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 180. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Homozygous or compound heterozygous mutation in the MOCS2 gene have been shown to cause molybdenum cofactor deficiency. In summary, although additional studies are required to fully establish its clinical significance, the p.Lys180ArgfsX31 variant is likely pathogenic. -

Jun 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Aug 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the MOCS2B gene (p.Lys180Argfs*31). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the MOCS2B protein and extend the protein by 21 additional amino acid residues. This variant is present in population databases (rs398122797, gnomAD 0.03%). This frameshift has been observed in individual(s) with molybdenum cofactor deficiency (PMID: 9459218, 10053004, 23436702, 33502714). This variant is also known as c.726_727delAA or 726del2. ClinVar contains an entry for this variant (Variation ID: 6108). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects MOCS2B function (PMID: 30810871). 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. -

Aug 19, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 9 amino acids are replaced with 30 different amino acids; Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 35192225, 10053004, 12754701, 23436702, 30810871, 33502714) -

Abnormality of metabolism/homeostasis Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs398122797; hg19: chr5-52394458;