20-50958927-G-T

Position:

• chr20-50958927-G-T

Variant summary

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

The NM_014484.5(MOCS3):​c.85G>T​(p.Ala29Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MOCS3 NM_014484.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

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]

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=0.18175355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MOCS3	NM_014484.5	c.85G>T	p.Ala29Ser	missense_variant	1/1	ENST00000244051.3	NP_055299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MOCS3	ENST00000244051.3	c.85G>T	p.Ala29Ser	missense_variant	1/1		NM_014484.5	ENSP00000244051	P1
DPM1	ENST00000683466.1	c.-341C>A		5_prime_UTR_variant	1/8			ENSP00000507404

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 02, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with MOCS3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 29 of the MOCS3 protein (p.Ala29Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.049
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.63	D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.058
Sift	Benign	0.36	T
Sift4G	Benign	0.56	T
Polyphen		0.44	B
Vest4		0.18
MutPred		0.26		Gain of phosphorylation at A29 (P = 0.0266);
MVP		0.83
MPC		0.50
ClinPred		0.34	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.082
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-49575464;