MARS1 p.Phe370Leu

Variant names:

• chr12-57500339-C-A
• NM_004990.4:c.1110C>A
• MARS1 p.Phe370Leu

Your query was ambiguous. Multiple possible variants found:

• chr12-57500339-C-A
• chr12-57500339-C-G
• chr12-57500337-T-C
• chr12-57500337-TTC-CTT
• chr12-57500337-TTC-CTA
• chr12-57500337-TTC-CTG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1_Moderate PM2 PP3_Strong

The NM_004990.4(MARS1):​c.1110C>A​(p.Phe370Leu) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MARS1 NM_004990.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41
• Publications: 0 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]

MARS1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2U

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal recessive spastic paraplegia type 70

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• spastic paraplegia 70, autosomal recessive

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• trichothiodystrophy 9, nonphotosensitive

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_004990.4 (MARS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

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.1110C>A	p.Phe370Leu	missense	Exon 10 of 21	NP_004981.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARS1	ENST00000262027.10	TSL:1 MANE Select	c.1110C>A	p.Phe370Leu	missense	Exon 10 of 21	ENSP00000262027.5	P56192-1
	MARS1	ENST00000948582.1		c.1110C>A	p.Phe370Leu	missense	Exon 10 of 22	ENSP00000618641.1
	MARS1	ENST00000948584.1		c.1110C>A	p.Phe370Leu	missense	Exon 10 of 22	ENSP00000618643.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		2.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
PromoterAI		0.0066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.92
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-57894122;