2-197705427-C-A

Variant summary

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

The NM_138395.4(MARS2):c.22C>A(p.Arg8Ser) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MARS2 NM_138395.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0620

Genes affected

MARS2 (HGNC:25133): (methionyl-tRNA synthetase 2, mitochondrial) This gene produces a mitochondrial methionyl-tRNA synthetase protein that is encoded by the nuclear genome and imported to the mitochondrion. This protein likely functions as a monomer and is predicted to localize to the mitochondrial matrix. Mutations in this gene are associated with the autosomal recessive neurodegenerative disease spastic ataxia-3 (SPAX3). [provided by RefSeq, Apr 2014]

(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=0.11344689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARS2	NM_138395.4	c.22C>A	p.Arg8Ser	missense_variant	1/1	ENST00000282276.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARS2	ENST00000282276.8	c.22C>A	p.Arg8Ser	missense_variant	1/1		NM_138395.4	P1
	ENST00000409845.1	n.166+6563C>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Jan 23, 2024

The c.22C>A (p.R8S) alteration is located in exon 1 (coding exon 1) of the MARS2 gene. This alteration results from a C to A substitution at nucleotide position 22, causing the arginine (R) at amino acid position 8 to be replaced by a serine (S). 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	0.20
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	7.2
Dann	Benign	0.92
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.079
Sift	Benign	0.043	D
Sift4G	Benign	0.13	T
Polyphen		0.12	B
Vest4		0.28
MutPred		0.39		Loss of MoRF binding (P = 0.0132);
MVP		0.42
MPC		0.53
ClinPred		0.078	T
GERP RS		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.10
gMVP		0.55

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: chr2-198570151;