7-30615951-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002047.4(GARS1):ā€‹c.1087C>Gā€‹(p.Pro363Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

1
11
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.85
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GARS1NM_002047.4 linkuse as main transcriptc.1087C>G p.Pro363Ala missense_variant 9/17 ENST00000389266.8 NP_002038.2 P41250-1
GARS1NM_001316772.1 linkuse as main transcriptc.925C>G p.Pro309Ala missense_variant 9/17 NP_001303701.1 P41250-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GARS1ENST00000389266.8 linkuse as main transcriptc.1087C>G p.Pro363Ala missense_variant 9/171 NM_002047.4 ENSP00000373918.3 P41250-1
GARS1ENST00000675651.1 linkuse as main transcriptc.1087C>G p.Pro363Ala missense_variant 9/17 ENSP00000502513.1 A0A6Q8PGZ8
GARS1ENST00000675810.1 linkuse as main transcriptc.985C>G p.Pro329Ala missense_variant 8/16 ENSP00000502743.1 A0A6Q8PHH9
GARS1ENST00000675693.1 linkuse as main transcriptc.919C>G p.Pro307Ala missense_variant 10/18 ENSP00000502174.1 A0A6Q8PGA8
GARS1ENST00000675051.1 linkuse as main transcriptc.886C>G p.Pro296Ala missense_variant 9/17 ENSP00000502296.1 A0A6Q8PGI6
GARS1ENST00000674815.1 linkuse as main transcriptc.718C>G p.Pro240Ala missense_variant 9/17 ENSP00000502799.1 A0A6Q8PGW4
GARS1ENST00000674851.1 linkuse as main transcriptc.718C>G p.Pro240Ala missense_variant 10/18 ENSP00000502451.1 A0A6Q8PGW4
GARS1ENST00000444666.6 linkuse as main transcriptn.1087C>G non_coding_transcript_exon_variant 9/183 ENSP00000415447.2 H7C443
GARS1ENST00000674616.1 linkuse as main transcriptn.*801C>G non_coding_transcript_exon_variant 10/18 ENSP00000502408.1 A0A6Q8PGT3
GARS1ENST00000674643.1 linkuse as main transcriptn.*187C>G non_coding_transcript_exon_variant 10/17 ENSP00000501636.1 A0A6Q8PF45
GARS1ENST00000674737.1 linkuse as main transcriptn.*425C>G non_coding_transcript_exon_variant 10/18 ENSP00000502464.1 A0A6Q8PGZ9
GARS1ENST00000674807.1 linkuse as main transcriptn.1087C>G non_coding_transcript_exon_variant 9/16 ENSP00000502814.1 A0A6Q8PFZ6
GARS1ENST00000675529.1 linkuse as main transcriptn.*957C>G non_coding_transcript_exon_variant 10/18 ENSP00000501655.1 A0A6Q8PFN0
GARS1ENST00000675859.1 linkuse as main transcriptn.1087C>G non_coding_transcript_exon_variant 9/15 ENSP00000502033.1 A0A6Q8PFZ6
GARS1ENST00000676088.1 linkuse as main transcriptn.*1029C>G non_coding_transcript_exon_variant 11/19 ENSP00000501884.1 A0A6Q8PFN0
GARS1ENST00000676140.1 linkuse as main transcriptn.*32C>G non_coding_transcript_exon_variant 9/17 ENSP00000502571.1 A0A6Q8PH49
GARS1ENST00000676164.1 linkuse as main transcriptn.*538C>G non_coding_transcript_exon_variant 9/17 ENSP00000501986.1 A0A6Q8PFV5
GARS1ENST00000676210.1 linkuse as main transcriptn.*376C>G non_coding_transcript_exon_variant 10/18 ENSP00000502373.1 A0A6Q8PGN7
GARS1ENST00000676259.1 linkuse as main transcriptn.*519C>G non_coding_transcript_exon_variant 9/17 ENSP00000501980.1 A0A6Q8PFU7
GARS1ENST00000676403.1 linkuse as main transcriptn.1087C>G non_coding_transcript_exon_variant 9/16 ENSP00000502681.1 A0A6Q8PHI7
GARS1ENST00000674616.1 linkuse as main transcriptn.*801C>G 3_prime_UTR_variant 10/18 ENSP00000502408.1 A0A6Q8PGT3
GARS1ENST00000674643.1 linkuse as main transcriptn.*187C>G 3_prime_UTR_variant 10/17 ENSP00000501636.1 A0A6Q8PF45
GARS1ENST00000674737.1 linkuse as main transcriptn.*425C>G 3_prime_UTR_variant 10/18 ENSP00000502464.1 A0A6Q8PGZ9
GARS1ENST00000675529.1 linkuse as main transcriptn.*957C>G 3_prime_UTR_variant 10/18 ENSP00000501655.1 A0A6Q8PFN0
GARS1ENST00000676088.1 linkuse as main transcriptn.*1029C>G 3_prime_UTR_variant 11/19 ENSP00000501884.1 A0A6Q8PFN0
GARS1ENST00000676140.1 linkuse as main transcriptn.*32C>G 3_prime_UTR_variant 9/17 ENSP00000502571.1 A0A6Q8PH49
GARS1ENST00000676164.1 linkuse as main transcriptn.*538C>G 3_prime_UTR_variant 9/17 ENSP00000501986.1 A0A6Q8PFV5
GARS1ENST00000676210.1 linkuse as main transcriptn.*376C>G 3_prime_UTR_variant 10/18 ENSP00000502373.1 A0A6Q8PGN7
GARS1ENST00000676259.1 linkuse as main transcriptn.*519C>G 3_prime_UTR_variant 9/17 ENSP00000501980.1 A0A6Q8PFU7

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152120
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461874
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152120
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

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
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 15, 2020This sequence change replaces proline with alanine at codon 363 of the GARS protein (p.Pro363Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. In summary, this variant has uncertain impact on GARS function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a GARS-related disease. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.065
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.68
D
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.038
D
MetaRNN
Uncertain
0.44
T
MetaSVM
Uncertain
-0.20
T
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-5.9
D
REVEL
Uncertain
0.45
Sift
Benign
0.045
D
Sift4G
Benign
0.12
T
Polyphen
0.0050
B
Vest4
0.38
MutPred
0.73
Gain of ubiquitination at K364 (P = 0.0632);
MVP
0.63
MPC
0.39
ClinPred
0.96
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.46
gMVP
0.64

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: rs267601479; hg19: chr7-30655567; API