NM_002047.4:c.875T>G

Variant names:

• chr7-30609724-T-G
• rs1064795123
• NM_002047.4:c.875T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_002047.4(GARS1):​c.875T>G​(p.Met292Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M292T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.19
• Publications: 7 publications found

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]

GARS1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 2D

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, type 5A

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Laboratory for Molecular Medicine
• spinal muscular atrophy, infantile, James type

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 421418.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 7-30609724-T-G is Pathogenic according to our data. Variant chr7-30609724-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 476764.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.875T>G	p.Met292Arg	missense_variant	Exon 7 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.713T>G	p.Met238Arg	missense_variant	Exon 7 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.875T>G	p.Met292Arg	missense_variant	Exon 7 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.875T>G	p.Met292Arg	missense_variant	Exon 7 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.773T>G	p.Met258Arg	missense_variant	Exon 6 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.707T>G	p.Met236Arg	missense_variant	Exon 8 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.674T>G	p.Met225Arg	missense_variant	Exon 7 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.506T>G	p.Met169Arg	missense_variant	Exon 7 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.506T>G	p.Met169Arg	missense_variant	Exon 8 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.875T>G		non_coding_transcript_exon_variant	Exon 7 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*589T>G		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.875T>G		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*213T>G		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.875T>G		non_coding_transcript_exon_variant	Exon 7 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*745T>G		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.875T>G		non_coding_transcript_exon_variant	Exon 7 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*817T>G		non_coding_transcript_exon_variant	Exon 9 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.875T>G		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*326T>G		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*164T>G		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*307T>G		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.875T>G		non_coding_transcript_exon_variant	Exon 7 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*589T>G		3_prime_UTR_variant	Exon 8 of 18			ENSP00000502408.1
GARS1	ENST00000674737.1	n.*213T>G		3_prime_UTR_variant	Exon 8 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*745T>G		3_prime_UTR_variant	Exon 8 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*817T>G		3_prime_UTR_variant	Exon 9 of 19			ENSP00000501884.1
GARS1	ENST00000676164.1	n.*326T>G		3_prime_UTR_variant	Exon 7 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*164T>G		3_prime_UTR_variant	Exon 8 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*307T>G		3_prime_UTR_variant	Exon 7 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Jun 21, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces methionine with arginine at codon 292 of the GARS protein (p.Met292Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been shown to arise de novo in an individual affected with Charcot-Marie-Tooth disease (CMT) type 2 (PMID: 26244500). In addition, it has been observed in 2 affected individuals (Invitae). This variant is also known as p.M238R in the literature. ClinVar contains an entry for this variant (Variation ID: 457156). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.088
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.75	T
PhyloP100		6.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.44
Sift	Benign	0.10	T
Sift4G	Benign	0.087	T
Polyphen		0.050	B
Vest4		0.84
MutPred		0.45		Gain of methylation at M292 (P = 0.0449);
MVP		0.55
MPC		0.98
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.80
gMVP		0.80
Mutation Taster		=18/82	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1064795123; hg19: chr7-30649340;