chr12-57488103-G-A

Variant names:

• chr12-57488103-G-A
• rs587777227
• NM_004990.4:c.13G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004990.4(MARS1):​c.13G>A​(p.Val5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MARS1 NM_004990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.94
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004990.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARS1	NM_004990.4	MANE Select	c.13G>A	p.Val5Met	missense	Exon 1 of 21	NP_004981.2
	ARHGAP9	NM_001319850.2		c.-204+509C>T		intron	N/A	NP_001306779.2	Q9BRR9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARS1	ENST00000262027.10	TSL:1 MANE Select	c.13G>A	p.Val5Met	missense	Exon 1 of 21	ENSP00000262027.5	P56192-1
	ARHGAP9	ENST00000393797.7	TSL:1	c.-204+509C>T		intron	N/A	ENSP00000377386.3	Q9BRR9-1
	MARS1	ENST00000948582.1		c.13G>A	p.Val5Met	missense	Exon 1 of 22	ENSP00000618641.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251154 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111976

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease axonal type 2U;C4225400:Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency (1)
1	-	-	Spastic paraplegia 70, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.051
Eigen_PC	Benign	0.012
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.73	N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.037	D
Polyphen		0.99	D
Vest4		0.58
MutPred		0.27		Gain of catalytic residue at V9 (P = 0)
MVP		0.78
MPC		0.38
ClinPred		0.61	D
GERP RS		3.4
PromoterAI		-0.31	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.21
gMVP		0.56
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs587777227; hg19: chr12-57881886;