rs201535531

Variant names:

• chr12-57488073-C-T
• rs201535531
• NM_004990.4:c.-18C>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_004990.4(MARS1):​c.-18C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,609,278 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: MARS1 NM_004990.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.60

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

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000387 (59/152314) while in subpopulation AMR AF= 0.00124 (19/15306). AF 95% confidence interval is 0.000812. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARS1	NM_004990.4	c.-18C>T		5_prime_UTR_variant	Exon 1 of 21	ENST00000262027.10	NP_004981.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARS1	ENST00000262027	c.-18C>T		5_prime_UTR_variant	Exon 1 of 21	1	NM_004990.4	ENSP00000262027.5

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000296 AC: 74 AN: 249934 Hom.: 0 AF XY: 0.000259 AC XY: 35 AN XY: 135100

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000697

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000426

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000396 AC: 577 AN: 1456964 Hom.: 1 Cov.: 31 AF XY: 0.000388 AC XY: 281 AN XY: 724966

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000784

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000473

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74474

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000521 Hom.: 0

Bravo AF: 0.000404

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MARS1 c.-18C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.00029 in 281306 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MARS1 causing Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency (0.00029 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.-18C>T in individuals affected with Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 424681). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary spastic paraplegia Uncertain:1

Mar 07, 2017

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs201535531; hg19: chr12-57881856;