7-30599995-G-C

Variant names:

• chr7-30599995-G-C
• rs797044855
• NM_002047.4:c.373G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_002047.4(GARS1):​c.373G>C​(p.Glu125Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E125G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-30599996-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.373G>C	p.Glu125Gln	missense_variant	Exon 3 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.211G>C	p.Glu71Gln	missense_variant	Exon 3 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.373G>C	p.Glu125Gln	missense_variant	Exon 3 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.373G>C	p.Glu125Gln	missense_variant	Exon 3 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.271G>C	p.Glu91Gln	missense_variant	Exon 2 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.205G>C	p.Glu69Gln	missense_variant	Exon 4 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.172G>C	p.Glu58Gln	missense_variant	Exon 3 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.4G>C	p.Glu2Gln	missense_variant	Exon 3 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.4G>C	p.Glu2Gln	missense_variant	Exon 4 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.373G>C		non_coding_transcript_exon_variant	Exon 3 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*87G>C		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.373G>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.373G>C		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.373G>C		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*243G>C		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.373G>C		non_coding_transcript_exon_variant	Exon 3 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*243G>C		non_coding_transcript_exon_variant	Exon 4 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.373G>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.373G>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.373G>C		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.373G>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.373G>C		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*87G>C		3_prime_UTR_variant	Exon 4 of 18			ENSP00000502408.1
GARS1	ENST00000675529.1	n.*243G>C		3_prime_UTR_variant	Exon 4 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*243G>C		3_prime_UTR_variant	Exon 4 of 19			ENSP00000501884.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Apr 01, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with GARS-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. A different missense substitution at this codon (p.Glu125Lys) has been determined to be pathogenic (PMID: 25356970). This suggests that the glutamic acid residue is critical for GARS protein function and that other missense substitutions at this position may also be pathogenic. 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glutamine at codon 125 of the GARS protein (p.Glu125Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.43	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.40		Loss of ubiquitination at K129 (P = 0.0432);
MVP		0.86
MPC		1.1
ClinPred		0.97	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.81

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: rs797044855; hg19: chr7-30639611;