7-30615898-A-G

Position:

• chr7-30615898-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_002047.4(GARS1):​c.1034A>G​(p.Glu345Gly) variant causes a missense, splice region 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. 12/20 in silico tools predict a damaging outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GARS1 NM_002047.4 missense, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.22

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 7-30615898-A-G is Pathogenic according to our data. Variant chr7-30615898-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 543246.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1034A>G	p.Glu345Gly	missense_variant, splice_region_variant	9/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.872A>G	p.Glu291Gly	missense_variant, splice_region_variant	9/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1034A>G	p.Glu345Gly	missense_variant, splice_region_variant	9/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1034A>G	p.Glu345Gly	missense_variant, splice_region_variant	9/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.932A>G	p.Glu311Gly	missense_variant, splice_region_variant	8/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.866A>G	p.Glu289Gly	missense_variant, splice_region_variant	10/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.833A>G	p.Glu278Gly	missense_variant, splice_region_variant	9/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.665A>G	p.Glu222Gly	missense_variant, splice_region_variant	9/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.665A>G	p.Glu222Gly	missense_variant, splice_region_variant	10/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1034A>G		splice_region_variant, non_coding_transcript_exon_variant	9/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*748A>G		splice_region_variant, non_coding_transcript_exon_variant	10/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*134A>G		splice_region_variant, non_coding_transcript_exon_variant	10/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*372A>G		splice_region_variant, non_coding_transcript_exon_variant	10/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1034A>G		splice_region_variant, non_coding_transcript_exon_variant	9/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*904A>G		splice_region_variant, non_coding_transcript_exon_variant	10/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1034A>G		splice_region_variant, non_coding_transcript_exon_variant	9/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*976A>G		splice_region_variant, non_coding_transcript_exon_variant	11/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.1032A>G		splice_region_variant, non_coding_transcript_exon_variant	9/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*485A>G		splice_region_variant, non_coding_transcript_exon_variant	9/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*323A>G		splice_region_variant, non_coding_transcript_exon_variant	10/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*466A>G		splice_region_variant, non_coding_transcript_exon_variant	9/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1034A>G		splice_region_variant, non_coding_transcript_exon_variant	9/16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*748A>G		3_prime_UTR_variant	10/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*134A>G		3_prime_UTR_variant	10/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*372A>G		3_prime_UTR_variant	10/18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*904A>G		3_prime_UTR_variant	10/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*976A>G		3_prime_UTR_variant	11/19			ENSP00000501884.1
GARS1	ENST00000676164.1	n.*485A>G		3_prime_UTR_variant	9/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*323A>G		3_prime_UTR_variant	10/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*466A>G		3_prime_UTR_variant	9/17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2020

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Glu345 amino acid residue in GARS. Other variant(s) that disrupt this residue have been observed in individuals with GARS-related conditions (PMID: 28708278), which suggests that this may be a clinically significant amino acid residue. 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 has been observed in individual(s) with Charcot-Marie-Tooth disease (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 543246). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glycine at codon 345 of the GARS protein (p.Glu345Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.93		Loss of stability (P = 0.0258);
MVP		0.95
MPC		1.2
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1554338641; hg19: chr7-30655514;