1-220761774-G-C

Position:

• chr1-220761774-G-C

Variant summary

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

The ENST00000366913.8(MTARC2):​c.563G>C​(p.Gly188Ala) 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: 32)
• Consequence: MTARC2 ENST00000366913.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

Genes affected

MTARC2 (HGNC:26064): (mitochondrial amidoxime reducing component 2) The protein encoded by this gene is an enzyme found in the outer mitochondrial membrane that reduces N-hydroxylated substrates. The encoded protein uses molybdenum as a cofactor and cytochrome b5 type B and NADH cytochrome b5 reductase as accessory proteins. One type of substrate used is N-hydroxylated nucleotide base analogues, which can be toxic to a cell. Other substrates include N(omega)-hydroxy-L-arginine (NOHA) and amidoxime prodrugs, which are activated by the encoded enzyme. Multiple transcript variants encoding the different isoforms have been found for this gene. [provided by RefSeq, Sep 2016]

MTARC2 (HGNC:):

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=0.093150675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTARC2	NM_017898.5	c.563G>C	p.Gly188Ala	missense_variant	3/8	ENST00000366913.8	NP_060368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTARC2	ENST00000366913.8	c.563G>C	p.Gly188Ala	missense_variant	3/8	1	NM_017898.5	ENSP00000355880.3
MTARC2	ENST00000359316.6	c.563G>C	p.Gly188Ala	missense_variant	3/5	1		ENSP00000352266.2
MTARC2	ENST00000425560.1	c.266G>C	p.Gly89Ala	missense_variant	2/4	3		ENSP00000416442.1
MTARC2	ENST00000496078.1	n.*10G>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.563G>C (p.G188A) alteration is located in exon 3 (coding exon 3) of the MARC2 gene. This alteration results from a G to C substitution at nucleotide position 563, causing the glycine (G) at amino acid position 188 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Benign	0.081
DEOGEN2	Benign	0.0049	.;T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.093	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.64	N;N;N
REVEL	Benign	0.067
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.045	B;B;.
Vest4		0.059
MutPred		0.55		Loss of ubiquitination at K193 (P = 0.0982);Loss of ubiquitination at K193 (P = 0.0982);.;
MVP		0.12
MPC		0.35
ClinPred		0.082	T
GERP RS		1.3
Varity_R		0.061
gMVP		0.38

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

Other links and lift over

dbSNP: rs1671444114; hg19: chr1-220935116;