12-57488095-G-C

Variant summary

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

The NM_004990.4(MARS1):c.5G>C(p.Arg2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MARS1 NM_004990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

Genes affected

MARS1 (HGNC:6898): (methionyl-tRNA synthetase 1) This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. The encoded protein is a component of the multi-tRNA synthetase complex and catalyzes the ligation of methionine to tRNA molecules. [provided by RefSeq, Jan 2011]

ARHGAP9 (HGNC:14130): (Rho GTPase activating protein 9) This gene encodes a member of the Rho-GAP family of GTPase activating proteins. The protein has substantial GAP activity towards several Rho-family GTPases in vitro, converting them to an inactive GDP-bound state. It is implicated in regulating adhesion of hematopoietic cells to the extracellular matrix. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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
MARS1	NM_004990.4	c.5G>C	p.Arg2Thr	missense_variant	1/21	ENST00000262027.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARS1	ENST00000262027.10	c.5G>C	p.Arg2Thr	missense_variant	1/21	1	NM_004990.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2U;C4225400:Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1939722). This variant has not been reported in the literature in individuals affected with MARS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 2 of the MARS protein (p.Arg2Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	21
Dann	Benign	0.93
DEOGEN2	Benign	0.19	T;.;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.35	T;T;T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.69	N;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.1	N;.;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.15	T;.;.;.
Sift4G	Benign	0.17	T;D;D;D
Polyphen		0.14	B;.;.;.
Vest4		0.68
MutPred		0.37		Gain of catalytic residue at F4 (P = 9e-04);Gain of catalytic residue at F4 (P = 9e-04);Gain of catalytic residue at F4 (P = 9e-04);Gain of catalytic residue at F4 (P = 9e-04);
MVP		0.80
MPC		0.36
ClinPred		0.66	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.36
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1166063337; hg19: chr12-57881878; COSMIC: COSV56259257; COSMIC: COSV56259257;