rs398122798

chr5-53101386-TTGAC-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004531.5(MOCS2):c.346_349del(p.Val116AsnfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: MOCS2 NM_004531.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.31

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 11 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 5-53101386-TTGAC-T is Pathogenic according to our data. Variant chr5-53101386-TTGAC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6110.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr5-53101386-TTGAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MOCS2	NM_004531.5	c.346_349del	p.Val116AsnfsTer3	frameshift_variant	5/7	ENST00000396954.8
MOCS2	NM_176806.4	c.*266_*269del		3_prime_UTR_variant	5/7	ENST00000450852.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MOCS2	ENST00000396954.8	c.346_349del	p.Val116AsnfsTer3	frameshift_variant	5/7	1	NM_004531.5	P1
MOCS2	ENST00000450852.8	c.*266_*269del		3_prime_UTR_variant	5/7	1	NM_176806.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000119 AC: 3 AN: 251314 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135820

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461660 Hom.: 0 AF XY: 0.0000248 AC XY: 18 AN XY: 727136

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74508

Gnomad4 AFR AF: 0.0000240

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 12, 2023

This sequence change creates a premature translational stop signal (p.Val116Asnfs*3) in the MOCS2B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MOCS2B are known to be pathogenic (PMID: 21031595). This variant is present in population databases (rs398122798, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with molybdenum cofactor deficiency (PMID: 10053004). This variant is also known as 533del4. ClinVar contains an entry for this variant (Variation ID: 6110). For these reasons, this variant has been classified as Pathogenic. -

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1999

- -

Combined molybdoflavoprotein enzyme deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs398122798; hg19: chr5-52397216;