rs751603831

chr6-39909055-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001358530.2(MOCS1):c.1150G>A(p.Glu384Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,610,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: MOCS1 NM_001358530.2 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 7.84

Genes affected

MOCS1 (HGNC:7190): (molybdenum cofactor synthesis 1) Molybdenum cofactor biosynthesis is a conserved pathway leading to the biological activation of molybdenum. The protein encoded by this gene is involved in this pathway. This gene was originally thought to produce a bicistronic mRNA with the potential to produce two proteins (MOCS1A and MOCS1B) from adjacent open reading frames. However, only the first open reading frame (MOCS1A) has been found to encode a protein from the putative bicistronic mRNA, whereas additional splice variants are likely to produce a fusion between the two open reading frames. This gene is defective in patients with molybdenum cofactor deficiency, type A. A related pseudogene has been identified on chromosome 16. [provided by RefSeq, Nov 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MOCS1	NM_001358530.2	c.1150G>A	p.Glu384Lys	missense_variant, splice_region_variant	10/11	ENST00000340692.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MOCS1	ENST00000340692.10	c.1150G>A	p.Glu384Lys	missense_variant, splice_region_variant	10/11	5	NM_001358530.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149486 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000248

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461384 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000252

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149486 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 72722

Gnomad4 AFR AF: 0.0000248

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: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A Pathogenic:1 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 06, 2017	The MOCS1 c.1150G>A (p.Gly384Ser) missense variant has been reported in one study and is found in a compound heterozygous state in one individual with molybdenum cofactor deficiency (Reiss et al. 1998). The p.Gly384Ser variant was absent from 50 control chromosomes and is reported at a frequency of 0.000067 in the European (non-Finnish) population of the Genome Aggregation Database, but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Expression analysis in E. coli found the p.Gly384Ser variant to have significantly reduced activity compared to wildtype (Hänzelmann et al. 2002). The p.Gly384 residue is conserved across mammals, plants, and bacteria (Reiss et al. 1998). Based on the evidence, the p.Gly384Ser variant is classified as a variant of unknown significance but suspicious for pathogenicity for molybdenum cofactor deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2022	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 384 of the MOCS1 protein (p.Gly384Ser). This variant is present in population databases (rs751603831, gnomAD 0.007%). This missense change has been observed in individual(s) with molybdenum cofactor deficiency (PMID: 9921896). ClinVar contains an entry for this variant (Variation ID: 534542). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MOCS1 function (PMID: 11891227). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 31, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant in c.1150G>A(p.Glu384Lys) in MOCS1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu384Lys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes and has an allele frequency of 0.003203% from gnomAD database. This variant has been reported to the ClinVar database as Uncertain Significance (VUS). The amino acid change p.Glu384Lys in MOCS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 384 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). The above variant has been observed in the spouse. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 26, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.024	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.27
Sift	Benign	0.17	T
Sift4G	Benign	0.47	T
Vest4		0.36
MutPred		0.75		Gain of MoRF binding (P = 0.0105);
MVP		0.54
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.17
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.64		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs751603831; hg19: chr6-39876831; COSMIC: COSV51310735; COSMIC: COSV51310735;