rs1555166943

Variant names:

• chr12-57498438-GTGGAACACCCTCT-CTC
• rs1555166943
• NM_004990.4:c.906_919delGTGGAACACCCTCTinsCTC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_004990.4(MARS1):​c.906_919delGTGGAACACCCTCTinsCTC​(p.Gln302HisfsTer8) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MARS1 NM_004990.4 frameshift, missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.44
• 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
• 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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 12-57498438-GTGGAACACCCTCT-CTC is Pathogenic according to our data. Variant chr12-57498438-GTGGAACACCCTCT-CTC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475434.

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.906_919delGTGGAACACCCTCTinsCTC	p.Gln302HisfsTer8	frameshift missense	Exon 9 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.906_919delGTGGAACACCCTCTinsCTC	p.Gln302HisfsTer8	frameshift missense	Exon 9 of 21	ENSP00000262027.5	P56192-1
	MARS1	ENST00000948582.1		c.906_919delGTGGAACACCCTCTinsCTC	p.Gln302HisfsTer8	frameshift missense	Exon 9 of 22	ENSP00000618641.1
	MARS1	ENST00000948584.1		c.906_919delGTGGAACACCCTCTinsCTC	p.Gln302HisfsTer8	frameshift missense	Exon 9 of 22	ENSP00000618643.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4

Splicing

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

Other links and lift over

dbSNP: rs1555166943; hg19: chr12-57892221;