rs1064795123

Positions:

• chr7-30609724-T-C
• chr7-30609724-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP5_Moderate BP4

The NM_002047.4(GARS1):​c.875T>C​(p.Met292Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M292R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.19

Genes affected

GARS1 (HGNC:4162): (glycyl-tRNA synthetase 1) This gene encodes glycyl-tRNA synthetase, one of the aminoacyl-tRNA synthetases that charge tRNAs with their cognate amino acids. The encoded enzyme is an (alpha)2 dimer which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a strand (size 9) in uniprot entity GARS_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002047.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-30609724-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 476764.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 7-30609724-T-C is Pathogenic according to our data. Variant chr7-30609724-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421418.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25831804). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GARS1	NM_002047.4	c.875T>C	p.Met292Thr	missense_variant	7/17	ENST00000389266.8
GARS1	NM_001316772.1	c.713T>C	p.Met238Thr	missense_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GARS1	ENST00000389266.8	c.875T>C	p.Met292Thr	missense_variant	7/17	1	NM_002047.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461190 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

The M292T variant in the GARS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 5900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M292T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in the same residue (M292R) has been reported (as M238R due to the use of alternative nomenclature) in association with Charcot Marie Tooth disease type 2 (Liao et al., 2015), supporting the functional importance of this residue of the protein. The M292T variant is a strong candidate for a pathogenic variant, however, the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.24
Sift	Benign	0.18	T
Sift4G	Benign	0.16	T
Polyphen		0.0060	B
Vest4		0.56
MutPred		0.38		Gain of phosphorylation at M292 (P = 0.041);
MVP		0.16
MPC		0.42
ClinPred		0.83	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.54
gMVP		0.61

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: rs1064795123; hg19: chr7-30649340;