rs121908605

Variant names:

• chr5-53098667-C-T
• rs121908605
• NM_004531.5:c.502G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_004531.5(MOCS2):​c.502G>A​(p.Glu168Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,459,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MOCS2 NM_004531.5 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.30
• Publications: 6 publications found

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]

MOCS2 Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 5-53098667-C-T is Pathogenic according to our data. Variant chr5-53098667-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6109.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOCS2	NM_004531.5	c.502G>A	p.Glu168Lys	missense_variant, splice_region_variant	Exon 7 of 7	ENST00000396954.8	NP_004522.1
MOCS2	NM_176806.4	c.*422G>A		splice_region_variant	Exon 7 of 7	ENST00000450852.8	NP_789776.1
MOCS2	NM_176806.4	c.*422G>A		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.502G>A	p.Glu168Lys	missense_variant, splice_region_variant	Exon 7 of 7	1	NM_004531.5	ENSP00000380157.3
MOCS2	ENST00000450852.8	c.*422G>A		splice_region_variant	Exon 7 of 7	1	NM_176806.4	ENSP00000411022.3
MOCS2	ENST00000450852.8	c.*422G>A		3_prime_UTR_variant	Exon 7 of 7	1	NM_176806.4	ENSP00000411022.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459142 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726144

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109664

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Jul 11, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		4.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.61		Gain of MoRF binding (P = 0.0019);
MVP		0.82
MPC		0.073
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.81
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908605; hg19: chr5-52394497;