Variant chr1-220781893-A-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_017898.5(MTARC2):c.1000A>C(p.Met334Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,614,016 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

MTARC2
NM_017898.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

Variant links:

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 links:

MTARC2 (HGNC:):

MTARC2 links:

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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=0.0051360726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTARC2	NM_017898.5 linkuse as main transcript	c.1000A>C	p.Met334Leu	missense_variant	7/8	ENST00000366913.8	NP_060368.2	Q969Z3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MTARC2	ENST00000366913.8 linkuse as main transcript	c.1000A>C	p.Met334Leu	missense_variant	7/8	1	NM_017898.5	ENSP00000355880.3	Q969Z3-1
MTARC2	ENST00000359316.6 linkuse as main transcript	c.751-2026A>C		intron_variant		1		ENSP00000352266.2	Q969Z3-2
MTARC2	ENST00000472447.1 linkuse as main transcript	n.394A>C		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000422

AC:

106

AN:

251390

Hom.:

AF XY:

0.000375

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00923

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000244

AC:

356

AN:

1461826

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

178

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00942

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000263

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00191

Alfa

AF:

0.000460

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000338

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2022

The c.1000A>C (p.M334L) alteration is located in exon 7 (coding exon 7) of the MARC2 gene. This alteration results from a A to C substitution at nucleotide position 1000, causing the methionine (M) at amino acid position 334 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

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.67

DEOGEN2

Benign

0.0067

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.39

M_CAP

Benign

0.0033

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.93

PrimateAI

Benign

0.46

PROVEAN

Benign

0.15

REVEL

Benign

0.025

Sift

Benign

0.37

Sift4G

Benign

0.34

Polyphen

0.0010

Vest4

0.26

MutPred

0.36

Loss of MoRF binding (P = 0.091);

MVP

0.13

MPC

0.24

ClinPred

0.0078

GERP RS

0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.044

gMVP

0.32

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over