rs1325522512

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002047.4(GARS1):c.1487A>G(p.Gln496Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.29

Publications

1 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1487A>G	p.Gln496Arg	missense_variant	Exon 12 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.1325A>G	p.Gln442Arg	missense_variant	Exon 12 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GARS1	ENST00000389266.8 link	c.1487A>G	p.Gln496Arg	missense_variant	Exon 12 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.1487A>G	p.Gln496Arg	missense_variant	Exon 12 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.1385A>G	p.Gln462Arg	missense_variant	Exon 11 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.1319A>G	p.Gln440Arg	missense_variant	Exon 13 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.1286A>G	p.Gln429Arg	missense_variant	Exon 12 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.1118A>G	p.Gln373Arg	missense_variant	Exon 12 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.1118A>G	p.Gln373Arg	missense_variant	Exon 13 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.1487A>G		non_coding_transcript_exon_variant	Exon 12 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*1201A>G		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*587A>G		non_coding_transcript_exon_variant	Exon 13 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*825A>G		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.1487A>G		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*1357A>G		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.1487A>G		non_coding_transcript_exon_variant	Exon 12 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*1429A>G		non_coding_transcript_exon_variant	Exon 14 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*432A>G		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*938A>G		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*776A>G		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*919A>G		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.1487A>G		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1 link	n.*1201A>G		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*587A>G		3_prime_UTR_variant	Exon 13 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*825A>G		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1 link	n.*1357A>G		3_prime_UTR_variant	Exon 13 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*1429A>G		3_prime_UTR_variant	Exon 14 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*432A>G		3_prime_UTR_variant	Exon 12 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*938A>G		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*776A>G		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*919A>G		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2

Uncertain:1

Apr 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GARS protein function. ClinVar contains an entry for this variant (Variation ID: 476751). This variant has not been reported in the literature in individuals affected with GARS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 496 of the GARS protein (p.Gln496Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.75

MetaSVM

Uncertain

-0.24

PhyloP100

9.3

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.61

Sift

Benign

0.23

Sift4G

Benign

0.18

Polyphen

0.0050

Vest4

0.88

MutPred

0.55

Gain of MoRF binding (P = 0.0249);

MVP

0.99

MPC

0.44

ClinPred

0.76

GERP RS

5.4

Varity_R

0.22

gMVP

0.31

Mutation Taster

=45/55

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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