chr5-53098602-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM4PP5_Very_Strong

The NM_004531.5(MOCS2):c.567A>C(p.Ter189Tyrext*?) 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.73

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM4

Stoplost variant in NM_004531.5 Downstream stopcodon found after 120 codons.

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_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53098602-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOCS2	NM_004531.5 link	c.567A>C	p.Ter189Tyrext*?	stop_lost	Exon 7 of 7	ENST00000396954.8	NP_004522.1	O96007A0A024QZS1
MOCS2	NM_176806.4 link	c.*487A>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000450852.8	NP_789776.1	O96033

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MOCS2	ENST00000396954.8 link	c.567A>C	p.Ter189Tyrext*?	stop_lost	Exon 7 of 7	1	NM_004531.5	ENSP00000380157.3		O96007
MOCS2	ENST00000450852 link	c.*487A>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_176806.4	ENSP00000411022.3		O96033

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000637

AC:

AN:

251248

AF XY:

0.0000589

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1460578

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33452

Gnomad4 AMR exome

AF:

0.000470

AC:

AN:

44710

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26118

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39618

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86226

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53410

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1110932

Gnomad4 Remaining exome

AF:

0.0000166

AC:

AN:

60348

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.000131

AC:

0.000130856

AN:

0.000130856

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; internal data). 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 gene product 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. -

Nov 11, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Normal stop codon changed to a Tyr codon, leading to the addition of 18 amino acids at the C-terminus; Published functional studies demonstrate that the extended protein created by this variant is functionally deleterious (PMID: 16021469); Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 16021469, 27535533) -

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B

Pathogenic:2

Oct 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.45

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

Vest4

0.010

GERP RS

2.8

Mutation Taster

=77/123

disease causing

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over