1-220763021-G-T

Variant summary

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

The NM_017898.5(MTARC2):c.721G>T(p.Val241Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 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 NM_017898.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.522

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTARC2	NM_017898.5	c.721G>T	p.Val241Leu	missense_variant	4/8	ENST00000366913.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTARC2	ENST00000366913.8	c.721G>T	p.Val241Leu	missense_variant	4/8	1	NM_017898.5	P1
MTARC2	ENST00000359316.6	c.721G>T	p.Val241Leu	missense_variant	4/5	1
MTARC2	ENST00000425560.1	c.424G>T	p.Val142Leu	missense_variant	3/4	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

Aug 02, 2021

The c.721G>T (p.V241L) alteration is located in exon 4 (coding exon 4) of the MARC2 gene. This alteration results from a G to T substitution at nucleotide position 721, causing the valine (V) at amino acid position 241 to be replaced by a leucine (L). 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	0.27
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.018
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	0.62	D;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.053	T;T;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.48	P;P;.
Vest4		0.19
MutPred		0.81		Loss of catalytic residue at V241 (P = 0.1249);Loss of catalytic residue at V241 (P = 0.1249);.;
MVP		0.58
MPC		0.26
ClinPred		0.41	T
GERP RS		2.6
Varity_R		0.055
gMVP		0.51

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: chr1-220936363;