chr12-57490377-GAG-AAA

Variant names:

• chr12-57490377-GAG-AAA
• NM_004990.4:c.661_663delGAGinsAAA
• MARS1 p.Glu221Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_004990.4(MARS1):c.661_663delGAGinsAAA (p.Glu221Lys) variant causes a missense, splice region change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E221K: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 420243)

• Frequency: Genomes: not found (cov: 32)
• Consequence: MARS1 NM_004990.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.05
• 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, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet
• trichothiodystrophy

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• autosomal recessive spastic paraplegia type 70

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• trichothiodystrophy 9, nonphotosensitive

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae)
• spastic paraplegia 70, autosomal recessive

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MARS1 NM_004990.4	MANE Select	c.661_663delGAGinsAAA p.Glu221Lys	missensesplice_region	N/A	Prot: NP_004981.2

MARS1 NM_004990.4

MANE Select

HGVSc / HGVSpc.661_663delGAGinsAAAp.Glu221Lys

Exon rankN/A

missensesplice_region

Prot: NP_004981.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MARS1 ENST00000262027.10	TSL:1MANE Select	c.650_652delGAGinsAAA p.Thr217Lys	missense	N/A	Prot: ENSP00000262027.5 UniProt:
	MARS1 ENST00000948582.1		c.650_652delGAGinsAAA p.Thr217Lys	missense	N/A	Prot: ENSP00000618641.1 UniProt:
	MARS1 ENST00000948584.1		c.650_652delGAGinsAAA p.Thr217Lys	missense	N/A	Prot: ENSP00000618643.1 UniProt:

MARS1 ENST00000262027.10

TSL:1MANE Select

HGVSc / HGVSpc.650_652delGAGinsAAAp.Thr217Lys

Exon rankN/A

missense

Prot: ENSP00000262027.5UniProt: P56192-1

MARS1 ENST00000948582.1

HGVSc / HGVSpc.650_652delGAGinsAAAp.Thr217Lys

Exon rankN/A

missense

Prot: ENSP00000618641.1UniProt: A0ACI8UHF3

MARS1 ENST00000948584.1

HGVSc / HGVSpc.650_652delGAGinsAAAp.Thr217Lys

Exon rankN/A

missense

Prot: ENSP00000618643.1UniProt: A0ACI8UHG3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	6.0

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr12-57884160;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar