rs1554338641

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_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. 13/21 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

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.22

Publications

0 publications found

Variant links:

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

GARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 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 VariationId is 543246.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 link	c.1034A>G	p.Glu345Gly	missense_variant, splice_region_variant	Exon 9 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.872A>G	p.Glu291Gly	missense_variant, splice_region_variant	Exon 9 of 17		NP_001303701.1

Ensembl

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Jan 07, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.94

PhyloP100

9.2

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.93

Loss of stability (P = 0.0258);

MVP

0.95

MPC

1.2

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.96

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over