rs140243105

chr6-39912909-C-Gchr6-39912909-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001358530.2(MOCS1):c.853G>C(p.Glu285Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E285K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MOCS1 NM_001358530.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14049947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MOCS1	NM_001358530.2	c.853G>C	p.Glu285Gln	missense_variant	7/11	ENST00000340692.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MOCS1	ENST00000340692.10	c.853G>C	p.Glu285Gln	missense_variant	7/11	5	NM_001358530.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251492 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 285 of the MOCS1 protein (p.Glu285Gln). This variant is present in population databases (rs140243105, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MOCS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1039056). 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	18
Dann	Benign	0.97
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.58	N;.;N
MutationTaster	Benign	0.88	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.68	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.051	T;T;T
Sift4G	Benign	0.073	T;T;T
Polyphen		0.0050	B;.;B
Vest4		0.25
MutPred		0.46		Loss of ubiquitination at K290 (P = 0.0432);.;Loss of ubiquitination at K290 (P = 0.0432);
MVP		0.77
ClinPred		0.17	T
GERP RS		4.0
Varity_R		0.12
gMVP		0.51

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: rs140243105; hg19: chr6-39880653;