20-50958850-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014484.5(MOCS3):ā€‹c.8C>Gā€‹(p.Ser3Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000693 in 1,587,660 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 (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000049 ( 0 hom. )

Consequence

MOCS3
NM_014484.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.470
Variant links:
Genes affected
MOCS3 (HGNC:15765): (molybdenum cofactor synthesis 3) Molybdenum cofactor (MoCo) is necessary for the function of all molybdoenzymes. The protein encoded by this gene adenylates and activates molybdopterin synthase, an enzyme required for biosynthesis of MoCo. This gene contains no introns. A pseudogene of this gene is present on chromosome 14. [provided by RefSeq, Nov 2012]
DPM1 (HGNC:3005): (dolichyl-phosphate mannosyltransferase subunit 1, catalytic) Dolichol-phosphate mannose (Dol-P-Man) serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum (ER). Lack of Dol-P-Man results in defective surface expression of GPI-anchored proteins. Dol-P-Man is synthesized from GDP-mannose and dolichol-phosphate on the cytosolic side of the ER by the enzyme dolichyl-phosphate mannosyltransferase. Human DPM1 lacks a carboxy-terminal transmembrane domain and signal sequence and is regulated by DPM2. Mutations in this gene are associated with congenital disorder of glycosylation type Ie. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.038144797).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MOCS3NM_014484.5 linkuse as main transcriptc.8C>G p.Ser3Cys missense_variant 1/1 ENST00000244051.3 NP_055299.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MOCS3ENST00000244051.3 linkuse as main transcriptc.8C>G p.Ser3Cys missense_variant 1/1 NM_014484.5 ENSP00000244051 P1
DPM1ENST00000683466.1 linkuse as main transcriptc.-264G>C 5_prime_UTR_variant 1/8 ENSP00000507404

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152172
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00000417
AC:
1
AN:
239756
Hom.:
0
AF XY:
0.00000764
AC XY:
1
AN XY:
130920
show subpopulations
Gnomad AFR exome
AF:
0.0000661
Gnomad AMR exome
AF:
0.00
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:
0.00000488
AC:
7
AN:
1435372
Hom.:
0
Cov.:
32
AF XY:
0.00000423
AC XY:
3
AN XY:
709442
show subpopulations
Gnomad4 AFR exome
AF:
0.000122
Gnomad4 AMR exome
AF:
0.0000234
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:
0.00000183
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152288
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.0000654
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
Alfa
AF:
0.0000284
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000166
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 18, 2023ClinVar contains an entry for this variant (Variation ID: 2076146). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with MOCS3-related conditions. This variant is present in population databases (rs187280062, gnomAD 0.009%). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3 of the MOCS3 protein (p.Ser3Cys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
17
DANN
Benign
0.93
DEOGEN2
Benign
0.12
T
Eigen
Benign
-0.84
Eigen_PC
Benign
-0.81
FATHMM_MKL
Benign
0.079
N
LIST_S2
Benign
0.49
T
M_CAP
Benign
0.066
D
MetaRNN
Benign
0.038
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.0
N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.10
N
REVEL
Benign
0.047
Sift
Uncertain
0.028
D
Sift4G
Uncertain
0.022
D
Polyphen
0.14
B
Vest4
0.10
MutPred
0.18
Gain of catalytic residue at M1 (P = 0.0016);
MVP
0.85
MPC
0.69
ClinPred
0.098
T
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.11
gMVP
0.36

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.

Other links and lift over

dbSNP: rs187280062; hg19: chr20-49575387; API