NM_002047.4:c.2145A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002047.4(GARS1):​c.2145A>G​(p.Thr715Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0399 in 1,608,902 control chromosomes in the GnomAD database, including 2,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.084 ( 1155 hom., cov: 31)
Exomes 𝑓: 0.035 ( 1684 hom. )

Consequence

GARS1
NM_002047.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.72
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.65).
BP6
Variant 7-30633785-A-G is Benign according to our data. Variant chr7-30633785-A-G is described in ClinVar as [Benign]. Clinvar id is 137443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30633785-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.72 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GARS1NM_002047.4 linkc.2145A>G p.Thr715Thr synonymous_variant Exon 17 of 17 ENST00000389266.8 NP_002038.2 P41250-1
GARS1NM_001316772.1 linkc.1983A>G p.Thr661Thr synonymous_variant Exon 17 of 17 NP_001303701.1 P41250-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GARS1ENST00000389266.8 linkc.2145A>G p.Thr715Thr synonymous_variant Exon 17 of 17 1 NM_002047.4 ENSP00000373918.3 P41250-1
GARS1ENST00000675651.1 linkc.2163A>G p.Thr721Thr synonymous_variant Exon 17 of 17 ENSP00000502513.1 A0A6Q8PGZ8
GARS1ENST00000675810.1 linkc.2043A>G p.Thr681Thr synonymous_variant Exon 16 of 16 ENSP00000502743.1 A0A6Q8PHH9
GARS1ENST00000675693.1 linkc.1977A>G p.Thr659Thr synonymous_variant Exon 18 of 18 ENSP00000502174.1 A0A6Q8PGA8
GARS1ENST00000675051.1 linkc.1944A>G p.Thr648Thr synonymous_variant Exon 17 of 17 ENSP00000502296.1 A0A6Q8PGI6
GARS1ENST00000674815.1 linkc.1776A>G p.Thr592Thr synonymous_variant Exon 17 of 17 ENSP00000502799.1 A0A6Q8PGW4
GARS1ENST00000674851.1 linkc.1776A>G p.Thr592Thr synonymous_variant Exon 18 of 18 ENSP00000502451.1 A0A6Q8PGW4
GARS1ENST00000444666.6 linkn.*566A>G non_coding_transcript_exon_variant Exon 18 of 18 3 ENSP00000415447.2 H7C443
GARS1ENST00000674616.1 linkn.*1859A>G non_coding_transcript_exon_variant Exon 18 of 18 ENSP00000502408.1 A0A6Q8PGT3
GARS1ENST00000674643.1 linkn.*1950A>G non_coding_transcript_exon_variant Exon 17 of 17 ENSP00000501636.1 A0A6Q8PF45
GARS1ENST00000674737.1 linkn.*1483A>G non_coding_transcript_exon_variant Exon 18 of 18 ENSP00000502464.1 A0A6Q8PGZ9
GARS1ENST00000674807.1 linkn.*418A>G non_coding_transcript_exon_variant Exon 16 of 16 ENSP00000502814.1 A0A6Q8PFZ6
GARS1ENST00000675529.1 linkn.*2015A>G non_coding_transcript_exon_variant Exon 18 of 18 ENSP00000501655.1 A0A6Q8PFN0
GARS1ENST00000675859.1 linkn.*324A>G non_coding_transcript_exon_variant Exon 15 of 15 ENSP00000502033.1 A0A6Q8PFZ6
GARS1ENST00000676088.1 linkn.*2087A>G non_coding_transcript_exon_variant Exon 19 of 19 ENSP00000501884.1 A0A6Q8PFN0
GARS1ENST00000676140.1 linkn.*1090A>G non_coding_transcript_exon_variant Exon 17 of 17 ENSP00000502571.1 A0A6Q8PH49
GARS1ENST00000676164.1 linkn.*1596A>G non_coding_transcript_exon_variant Exon 17 of 17 ENSP00000501986.1 A0A6Q8PFV5
GARS1ENST00000676210.1 linkn.*1434A>G non_coding_transcript_exon_variant Exon 18 of 18 ENSP00000502373.1 A0A6Q8PGN7
GARS1ENST00000676259.1 linkn.*1577A>G non_coding_transcript_exon_variant Exon 17 of 17 ENSP00000501980.1 A0A6Q8PFU7
GARS1ENST00000676403.1 linkn.*230A>G non_coding_transcript_exon_variant Exon 16 of 16 ENSP00000502681.1 A0A6Q8PHI7
GARS1ENST00000444666.6 linkn.*566A>G 3_prime_UTR_variant Exon 18 of 18 3 ENSP00000415447.2 H7C443
GARS1ENST00000674616.1 linkn.*1859A>G 3_prime_UTR_variant Exon 18 of 18 ENSP00000502408.1 A0A6Q8PGT3
GARS1ENST00000674643.1 linkn.*1950A>G 3_prime_UTR_variant Exon 17 of 17 ENSP00000501636.1 A0A6Q8PF45
GARS1ENST00000674737.1 linkn.*1483A>G 3_prime_UTR_variant Exon 18 of 18 ENSP00000502464.1 A0A6Q8PGZ9
GARS1ENST00000674807.1 linkn.*418A>G 3_prime_UTR_variant Exon 16 of 16 ENSP00000502814.1 A0A6Q8PFZ6
GARS1ENST00000675529.1 linkn.*2015A>G 3_prime_UTR_variant Exon 18 of 18 ENSP00000501655.1 A0A6Q8PFN0
GARS1ENST00000675859.1 linkn.*324A>G 3_prime_UTR_variant Exon 15 of 15 ENSP00000502033.1 A0A6Q8PFZ6
GARS1ENST00000676088.1 linkn.*2087A>G 3_prime_UTR_variant Exon 19 of 19 ENSP00000501884.1 A0A6Q8PFN0
GARS1ENST00000676140.1 linkn.*1090A>G 3_prime_UTR_variant Exon 17 of 17 ENSP00000502571.1 A0A6Q8PH49
GARS1ENST00000676164.1 linkn.*1596A>G 3_prime_UTR_variant Exon 17 of 17 ENSP00000501986.1 A0A6Q8PFV5
GARS1ENST00000676210.1 linkn.*1434A>G 3_prime_UTR_variant Exon 18 of 18 ENSP00000502373.1 A0A6Q8PGN7
GARS1ENST00000676259.1 linkn.*1577A>G 3_prime_UTR_variant Exon 17 of 17 ENSP00000501980.1 A0A6Q8PFU7
GARS1ENST00000676403.1 linkn.*230A>G 3_prime_UTR_variant Exon 16 of 16 ENSP00000502681.1 A0A6Q8PHI7

Frequencies

GnomAD3 genomes
AF:
0.0842
AC:
12779
AN:
151840
Hom.:
1146
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.224
Gnomad AMI
AF:
0.155
Gnomad AMR
AF:
0.0512
Gnomad ASJ
AF:
0.0228
Gnomad EAS
AF:
0.000581
Gnomad SAS
AF:
0.00479
Gnomad FIN
AF:
0.0123
Gnomad MID
AF:
0.0886
Gnomad NFE
AF:
0.0325
Gnomad OTH
AF:
0.0680
GnomAD3 exomes
AF:
0.0362
AC:
9044
AN:
249520
Hom.:
524
AF XY:
0.0329
AC XY:
4453
AN XY:
135374
show subpopulations
Gnomad AFR exome
AF:
0.225
Gnomad AMR exome
AF:
0.0280
Gnomad ASJ exome
AF:
0.0255
Gnomad EAS exome
AF:
0.000278
Gnomad SAS exome
AF:
0.00778
Gnomad FIN exome
AF:
0.0133
Gnomad NFE exome
AF:
0.0318
Gnomad OTH exome
AF:
0.0340
GnomAD4 exome
AF:
0.0353
AC:
51393
AN:
1456946
Hom.:
1684
Cov.:
42
AF XY:
0.0340
AC XY:
24607
AN XY:
724742
show subpopulations
Gnomad4 AFR exome
AF:
0.234
Gnomad4 AMR exome
AF:
0.0317
Gnomad4 ASJ exome
AF:
0.0243
Gnomad4 EAS exome
AF:
0.000152
Gnomad4 SAS exome
AF:
0.00831
Gnomad4 FIN exome
AF:
0.0140
Gnomad4 NFE exome
AF:
0.0335
Gnomad4 OTH exome
AF:
0.0443
GnomAD4 genome
AF:
0.0844
AC:
12819
AN:
151956
Hom.:
1155
Cov.:
31
AF XY:
0.0820
AC XY:
6090
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.224
Gnomad4 AMR
AF:
0.0510
Gnomad4 ASJ
AF:
0.0228
Gnomad4 EAS
AF:
0.000582
Gnomad4 SAS
AF:
0.00501
Gnomad4 FIN
AF:
0.0123
Gnomad4 NFE
AF:
0.0325
Gnomad4 OTH
AF:
0.0673
Alfa
AF:
0.0366
Hom.:
106
Bravo
AF:
0.0945
Asia WGS
AF:
0.0210
AC:
74
AN:
3478
EpiCase
AF:
0.0358
EpiControl
AF:
0.0337

ClinVar

Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 28, 2014
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Benign:1
-
Molecular Genetics Laboratory, London Health Sciences Centre
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Distal spinal muscular atrophy Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 2 Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
Feb 29, 2016
Mayo Clinic Laboratories, Mayo Clinic
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2D Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Neuronopathy, distal hereditary motor, type 5A Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.65
CADD
Benign
0.57
DANN
Benign
0.70

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4593; hg19: chr7-30673401; COSMIC: COSV66828907; COSMIC: COSV66828907; API