rs121908609

chr5-53098602-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_004531.5(MOCS2):c.567A>C(p.Ter189TyrextTer18) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,612,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: MOCS2 NM_004531.5 stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.73

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-53098602-T-G is Pathogenic according to our data. Variant chr5-53098602-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6115.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-53098602-T-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.451609).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MOCS2	NM_004531.5	c.567A>C	p.Ter189TyrextTer18	stop_lost	7/7	ENST00000396954.8
MOCS2	NM_176806.4	c.*487A>C		3_prime_UTR_variant	7/7	ENST00000450852.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MOCS2	ENST00000396954.8	c.567A>C	p.Ter189TyrextTer18	stop_lost	7/7	1	NM_004531.5	P1
MOCS2	ENST00000450852.8	c.*487A>C		3_prime_UTR_variant	7/7	1	NM_176806.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251248 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1460578 Hom.: 0 Cov.: 29 AF XY: 0.0000165 AC XY: 12 AN XY: 726682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 18, 2023

This sequence change disrupts the translational stop signal of the MOCS2B mRNA. It is expected to extend the length of the MOCS2B protein by 18 additional amino acid residues. This variant is present in population databases (rs121908609, gnomAD 0.05%). This protein extension has been observed in individual(s) with clinical features of molybdenum cofactor deficiency (PMID: 16021469; Invitae). This variant is also known as X189Y. ClinVar contains an entry for this variant (Variation ID: 6115). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this protein extension affects MOCS2B function (PMID: 16021469). 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. -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	7.8
Dann	Benign	0.79
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.014
FATHMM_MKL	Benign	0.60	D
MutationTaster	Benign	4.6e-12	A;A;A;A;A;A;A
Vest4		0.010
GERP RS		2.8

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: rs121908609; hg19: chr5-52394432;