Genetic Variant MTARC1:p.Leu15His (chr1-220786988-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_022746.4(MTARC1):c.44T>A(p.Leu15His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000772 in 1,282,914 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00079 ( 1 hom. )

Consequence

MTARC1
NM_022746.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.785

Variant links:

Genes affected

MTARC1 (HGNC:26189): (mitochondrial amidoxime reducing component 1) Enables molybdenum ion binding activity; molybdopterin cofactor binding activity; and oxidoreductase activity, acting on other nitrogenous compounds as donors. Contributes to nitrite reductase (NO-forming) activity. Involved in cellular detoxification of nitrogen compound; nitrate metabolic process; and nitric oxide biosynthetic process. Located in mitochondrion. Part of nitric-oxide synthase complex. [provided by Alliance of Genome Resources, Apr 2022]

MTARC1 links:

ENSG00000286231 (HGNC:):

ENSG00000286231 links:

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=0.011279255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTARC1	NM_022746.4 link	c.44T>A	p.Leu15His	missense_variant	Exon 1 of 7	ENST00000366910.10	NP_073583.3	Q5VT66-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTARC1	ENST00000366910.10 link	c.44T>A	p.Leu15His	missense_variant	Exon 1 of 7	1	NM_022746.4	ENSP00000355877.5		Q5VT66-1
ENSG00000286231	ENST00000651706.1 link	n.-2T>A		upstream_gene_variant				ENSP00000499157.1		A0A494C1P3

Frequencies

GnomAD3 genomes

AF:

0.000651

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000530

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000302

AC:

AN:

3310

Hom.:

AF XY:

0.00

AC XY:

AN XY:

1908

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000789

AC:

892

AN:

1130770

Hom.:

Cov.:

AF XY:

0.000770

AC XY:

419

AN XY:

543994

show subpopulations

Gnomad4 AFR exome

AF:

0.0000871

Gnomad4 AMR exome

AF:

0.000469

Gnomad4 ASJ exome

AF:

0.00921

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000372

Gnomad4 NFE exome

AF:

0.000718

Gnomad4 OTH exome

AF:

0.00138

GnomAD4 genome

AF:

0.000651

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000530

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000693

Hom.:

Bravo

AF:

0.000657

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000116

AC:

Asia WGS

AF:

0.000870

AC:

AN:

3462

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.44T>A (p.L15H) alteration is located in exon 1 (coding exon 1) of the MARC1 gene. This alteration results from a T to A substitution at nucleotide position 44, causing the leucine (L) at amino acid position 15 to be replaced by a histidine (H). 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

0.087

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.010

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.38

M_CAP

Benign

0.028

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.58

REVEL

Benign

0.033

Sift

Benign

0.031

Sift4G

Benign

0.55

Polyphen

0.84

Vest4

0.29

MVP

0.28

MPC

0.22

ClinPred

0.048

GERP RS

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.072

gMVP

0.37

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