7-30598875-G-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_002047.4(GARS1):​c.302G>A​(p.Arg101His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R101C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

5
6
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 9.10

Publications

12 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6
Variant 7-30598875-G-A is Benign according to our data. Variant chr7-30598875-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 245685.
BS1
Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000236 (36/152300) while in subpopulation AMR AF = 0.000588 (9/15304). AF 95% confidence interval is 0.000306. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GARS1NM_002047.4 linkc.302G>A p.Arg101His missense_variant Exon 2 of 17 ENST00000389266.8 NP_002038.2 P41250-1
GARS1NM_001316772.1 linkc.140G>A p.Arg47His missense_variant Exon 2 of 17 NP_001303701.1 P41250-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GARS1ENST00000389266.8 linkc.302G>A p.Arg101His missense_variant Exon 2 of 17 1 NM_002047.4 ENSP00000373918.3 P41250-1
GARS1ENST00000675651.1 linkc.302G>A p.Arg101His missense_variant Exon 2 of 17 ENSP00000502513.1 A0A6Q8PGZ8
GARS1ENST00000675693.1 linkc.134G>A p.Arg45His missense_variant Exon 3 of 18 ENSP00000502174.1 A0A6Q8PGA8
GARS1ENST00000675051.1 linkc.101G>A p.Arg34His missense_variant Exon 2 of 17 ENSP00000502296.1 A0A6Q8PGI6
GARS1ENST00000444666.6 linkn.302G>A non_coding_transcript_exon_variant Exon 2 of 18 3 ENSP00000415447.2 H7C443
GARS1ENST00000674616.1 linkn.302G>A non_coding_transcript_exon_variant Exon 2 of 18 ENSP00000502408.1 A0A6Q8PGT3
GARS1ENST00000674643.1 linkn.302G>A non_coding_transcript_exon_variant Exon 2 of 17 ENSP00000501636.1 A0A6Q8PF45
GARS1ENST00000674737.1 linkn.302G>A non_coding_transcript_exon_variant Exon 2 of 18 ENSP00000502464.1 A0A6Q8PGZ9
GARS1ENST00000674807.1 linkn.302G>A non_coding_transcript_exon_variant Exon 2 of 16 ENSP00000502814.1 A0A6Q8PFZ6
GARS1ENST00000675529.1 linkn.*172G>A non_coding_transcript_exon_variant Exon 3 of 18 ENSP00000501655.1 A0A6Q8PFN0
GARS1ENST00000675859.1 linkn.302G>A non_coding_transcript_exon_variant Exon 2 of 15 ENSP00000502033.1 A0A6Q8PFZ6
GARS1ENST00000676088.1 linkn.*172G>A non_coding_transcript_exon_variant Exon 3 of 19 ENSP00000501884.1 A0A6Q8PFN0
GARS1ENST00000676140.1 linkn.302G>A non_coding_transcript_exon_variant Exon 2 of 17 ENSP00000502571.1 A0A6Q8PH49
GARS1ENST00000676164.1 linkn.302G>A non_coding_transcript_exon_variant Exon 2 of 17 ENSP00000501986.1 A0A6Q8PFV5
GARS1ENST00000676210.1 linkn.302G>A non_coding_transcript_exon_variant Exon 2 of 18 ENSP00000502373.1 A0A6Q8PGN7
GARS1ENST00000676259.1 linkn.302G>A non_coding_transcript_exon_variant Exon 2 of 17 ENSP00000501980.1 A0A6Q8PFU7
GARS1ENST00000676403.1 linkn.302G>A non_coding_transcript_exon_variant Exon 2 of 16 ENSP00000502681.1 A0A6Q8PHI7
GARS1ENST00000674815.1 linkc.-68G>A 5_prime_UTR_variant Exon 2 of 17 ENSP00000502799.1 A0A6Q8PGW4
GARS1ENST00000674851.1 linkc.-68G>A 5_prime_UTR_variant Exon 3 of 18 ENSP00000502451.1 A0A6Q8PGW4
GARS1ENST00000675529.1 linkn.*172G>A 3_prime_UTR_variant Exon 3 of 18 ENSP00000501655.1 A0A6Q8PFN0
GARS1ENST00000676088.1 linkn.*172G>A 3_prime_UTR_variant Exon 3 of 19 ENSP00000501884.1 A0A6Q8PFN0
GARS1ENST00000675810.1 linkc.223-1072G>A intron_variant Intron 1 of 15 ENSP00000502743.1 A0A6Q8PHH9

Frequencies

GnomAD3 genomes
AF:
0.000237
AC:
36
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000367
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000345
AC:
86
AN:
249370
AF XY:
0.000355
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000348
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000592
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.000274
AC:
401
AN:
1461678
Hom.:
0
Cov.:
31
AF XY:
0.000267
AC XY:
194
AN XY:
727146
show subpopulations
African (AFR)
AF:
0.0000598
AC:
2
AN:
33472
American (AMR)
AF:
0.000313
AC:
14
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.0000928
AC:
8
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
0.000347
AC:
2
AN:
5768
European-Non Finnish (NFE)
AF:
0.000324
AC:
360
AN:
1111850
Other (OTH)
AF:
0.000248
AC:
15
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.466
Heterozygous variant carriers
0
21
42
63
84
105
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000236
AC:
36
AN:
152300
Hom.:
0
Cov.:
32
AF XY:
0.000228
AC XY:
17
AN XY:
74476
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41548
American (AMR)
AF:
0.000588
AC:
9
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.0000942
AC:
1
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000368
AC:
25
AN:
68024
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
3
6
10
13
16
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000439
Hom.:
0
Bravo
AF:
0.000280
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000244
AC:
2
ExAC
AF:
0.000381
AC:
46
EpiCase
AF:
0.000491
EpiControl
AF:
0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

GARS1: BS2 -

Nov 17, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Reported as a variant of unknown significance in individuals tested by an outside laboratory suspected of having Charcot-Marie-Tooth disease (DiVincenzo et al., 2014; Nam et al., 2021; Volodarsky et al., 2021); Identified previously in the heterozygous state in two individuals with neuropathy (Antoniadi et al., 2015; Apellniz-Ruiz et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27582484, 28166811, 34813128, 32028661, 34426522, 29520015, 32376792, 25614874, 26392352) -

Dec 29, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1Benign:1
Apr 17, 2023
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Mar 21, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: GARS1 c.302G>A (p.Arg101His) results in a non-conservative amino acid change located in the WHEP-TRS domain (IPR000738) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 280760 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.302G>A has been reported in the literature in individuals affected with neuropathy, CMT, or ALS without strong evidence of causality (e.g. Antoniadi_2015, Apellaniz-Ruiz_2017, Pensato_2020, Volodarsky_2021, Nam_2022). These reports do not provide unequivocal conclusions about association of the variant with GARS1-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant does not result in aberrant GlyRS-HDAC6 interaction (Mo_2018). The following publications have been ascertained in the context of this evaluation (PMID: 26392352, 27582484, 29520015, 32028661, 32376792, 34813128). ClinVar contains an entry for this variant (Variation ID: 245685). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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
Dec 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 2D Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.090
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.42
T
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Benign
0.014
T
MetaRNN
Uncertain
0.52
D
MetaSVM
Benign
-0.70
T
PhyloP100
9.1
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-4.4
D
REVEL
Uncertain
0.34
Sift
Benign
0.053
T
Sift4G
Benign
0.35
T
Polyphen
1.0
D
Vest4
0.88
MVP
0.49
MPC
0.57
ClinPred
0.47
T
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.62
gMVP
0.65
Mutation Taster
=28/72
disease causing

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

Other links and lift over

dbSNP: rs200887429; hg19: chr7-30638491; COSMIC: COSV66828540; COSMIC: COSV66828540; API