rs35843015

chr12-57516549-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_004990.4(MARS1):c.2671C>T(p.Pro891Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,597,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P891L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: MARS1 NM_004990.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.96

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]

DDIT3 (HGNC:2726): (DNA damage inducible transcript 3) This gene encodes a member of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, such as C/EBP and LAP (liver activator protein), and preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis, is activated by endoplasmic reticulum stress, and promotes apoptosis. Fusion of this gene and FUS on chromosome 16 or EWSR1 on chromosome 22 induced by translocation generates chimeric proteins in myxoid liposarcomas or Ewing sarcoma. Multiple alternatively spliced transcript variants encoding two isoforms with different length have been identified. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013292581).
• BP6: Variant 12-57516549-C-T is Benign according to our data. Variant chr12-57516549-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542174.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000598 (91/152252) while in subpopulation AFR AF= 0.0019 (79/41548). AF 95% confidence interval is 0.00156. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARS1	NM_004990.4	c.2671C>T	p.Pro891Ser	missense_variant	21/21	ENST00000262027.10
DDIT3	NM_004083.6			downstream_gene_variant		ENST00000346473.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARS1	ENST00000262027.10	c.2671C>T	p.Pro891Ser	missense_variant	21/21	1	NM_004990.4	P1
DDIT3	ENST00000346473.8			downstream_gene_variant		1	NM_004083.6	P1

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000167 AC: 39 AN: 234196 Hom.: 0 AF XY: 0.000150 AC XY: 19 AN XY: 126858

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.000236

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: 0.0000276

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000658 AC: 95 AN: 1444860 Hom.: 0 Cov.: 32 AF XY: 0.0000626 AC XY: 45 AN XY: 718642

Gnomad4 AFR exome AF: 0.00178

Gnomad4 AMR exome AF: 0.000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000993

Gnomad4 OTH exome AF: 0.000252

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74434

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.000706

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000198 AC: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 13, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2023	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Identified in an individual with hereditary spastic paraplegia, but segregation information was not provided (Panwala et al., 2022); This variant is associated with the following publications: (PMID: 35303589) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth disease axonal type 2U;C4225400:Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

MARS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	19
Dann	Benign	0.91
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.17
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.55	D
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.023
Sift	Benign	0.81	T;D
Sift4G	Benign	0.20	T;T
Polyphen		0.012	B;.
Vest4		0.14
MVP		0.50
MPC		0.25
ClinPred		0.010	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.089

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

Publications

LitVar

Other links and lift over

dbSNP: rs35843015; hg19: chr12-57910332;