rs1060502838

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_002047.4(GARS1):ā€‹c.1415A>Gā€‹(p.His472Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 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 Pathogenic (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

15
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4U:3O:1

Conservation

PhyloP100: 9.29
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 7-30621448-A-G is Pathogenic according to our data. Variant chr7-30621448-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 410314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30621448-A-G is described in Lovd as [Pathogenic]. Variant chr7-30621448-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GARS1NM_002047.4 linkuse as main transcriptc.1415A>G p.His472Arg missense_variant 11/17 ENST00000389266.8 NP_002038.2 P41250-1
GARS1NM_001316772.1 linkuse as main transcriptc.1253A>G p.His418Arg missense_variant 11/17 NP_001303701.1 P41250-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GARS1ENST00000389266.8 linkuse as main transcriptc.1415A>G p.His472Arg missense_variant 11/171 NM_002047.4 ENSP00000373918.3 P41250-1
GARS1ENST00000675651.1 linkuse as main transcriptc.1415A>G p.His472Arg missense_variant 11/17 ENSP00000502513.1 A0A6Q8PGZ8
GARS1ENST00000675810.1 linkuse as main transcriptc.1313A>G p.His438Arg missense_variant 10/16 ENSP00000502743.1 A0A6Q8PHH9
GARS1ENST00000675693.1 linkuse as main transcriptc.1247A>G p.His416Arg missense_variant 12/18 ENSP00000502174.1 A0A6Q8PGA8
GARS1ENST00000675051.1 linkuse as main transcriptc.1214A>G p.His405Arg missense_variant 11/17 ENSP00000502296.1 A0A6Q8PGI6
GARS1ENST00000674815.1 linkuse as main transcriptc.1046A>G p.His349Arg missense_variant 11/17 ENSP00000502799.1 A0A6Q8PGW4
GARS1ENST00000674851.1 linkuse as main transcriptc.1046A>G p.His349Arg missense_variant 12/18 ENSP00000502451.1 A0A6Q8PGW4
GARS1ENST00000444666.6 linkuse as main transcriptn.1415A>G non_coding_transcript_exon_variant 11/183 ENSP00000415447.2 H7C443
GARS1ENST00000674616.1 linkuse as main transcriptn.*1129A>G non_coding_transcript_exon_variant 12/18 ENSP00000502408.1 A0A6Q8PGT3
GARS1ENST00000674643.1 linkuse as main transcriptn.*515A>G non_coding_transcript_exon_variant 12/17 ENSP00000501636.1 A0A6Q8PF45
GARS1ENST00000674737.1 linkuse as main transcriptn.*753A>G non_coding_transcript_exon_variant 12/18 ENSP00000502464.1 A0A6Q8PGZ9
GARS1ENST00000674807.1 linkuse as main transcriptn.1415A>G non_coding_transcript_exon_variant 11/16 ENSP00000502814.1 A0A6Q8PFZ6
GARS1ENST00000675529.1 linkuse as main transcriptn.*1285A>G non_coding_transcript_exon_variant 12/18 ENSP00000501655.1 A0A6Q8PFN0
GARS1ENST00000675859.1 linkuse as main transcriptn.1415A>G non_coding_transcript_exon_variant 11/15 ENSP00000502033.1 A0A6Q8PFZ6
GARS1ENST00000676088.1 linkuse as main transcriptn.*1357A>G non_coding_transcript_exon_variant 13/19 ENSP00000501884.1 A0A6Q8PFN0
GARS1ENST00000676140.1 linkuse as main transcriptn.*360A>G non_coding_transcript_exon_variant 11/17 ENSP00000502571.1 A0A6Q8PH49
GARS1ENST00000676164.1 linkuse as main transcriptn.*866A>G non_coding_transcript_exon_variant 11/17 ENSP00000501986.1 A0A6Q8PFV5
GARS1ENST00000676210.1 linkuse as main transcriptn.*704A>G non_coding_transcript_exon_variant 12/18 ENSP00000502373.1 A0A6Q8PGN7
GARS1ENST00000676259.1 linkuse as main transcriptn.*847A>G non_coding_transcript_exon_variant 11/17 ENSP00000501980.1 A0A6Q8PFU7
GARS1ENST00000676403.1 linkuse as main transcriptn.1415A>G non_coding_transcript_exon_variant 11/16 ENSP00000502681.1 A0A6Q8PHI7
GARS1ENST00000674616.1 linkuse as main transcriptn.*1129A>G 3_prime_UTR_variant 12/18 ENSP00000502408.1 A0A6Q8PGT3
GARS1ENST00000674643.1 linkuse as main transcriptn.*515A>G 3_prime_UTR_variant 12/17 ENSP00000501636.1 A0A6Q8PF45
GARS1ENST00000674737.1 linkuse as main transcriptn.*753A>G 3_prime_UTR_variant 12/18 ENSP00000502464.1 A0A6Q8PGZ9
GARS1ENST00000675529.1 linkuse as main transcriptn.*1285A>G 3_prime_UTR_variant 12/18 ENSP00000501655.1 A0A6Q8PFN0
GARS1ENST00000676088.1 linkuse as main transcriptn.*1357A>G 3_prime_UTR_variant 13/19 ENSP00000501884.1 A0A6Q8PFN0
GARS1ENST00000676140.1 linkuse as main transcriptn.*360A>G 3_prime_UTR_variant 11/17 ENSP00000502571.1 A0A6Q8PH49
GARS1ENST00000676164.1 linkuse as main transcriptn.*866A>G 3_prime_UTR_variant 11/17 ENSP00000501986.1 A0A6Q8PFV5
GARS1ENST00000676210.1 linkuse as main transcriptn.*704A>G 3_prime_UTR_variant 12/18 ENSP00000502373.1 A0A6Q8PGN7
GARS1ENST00000676259.1 linkuse as main transcriptn.*847A>G 3_prime_UTR_variant 11/17 ENSP00000501980.1 A0A6Q8PFU7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461878
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4Uncertain:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neuronopathy, distal hereditary motor, type 5A Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 2014- -
Pathogenic, no assertion criteria providedclinical testingInstitute of Human Genetics, Cologne UniversityApr 25, 2018- -
Charcot-Marie-Tooth disease type 2D Uncertain:1Other:1
not provided, no classification providedliterature onlyGeneReviews-GARS1-HMSN (exclusively dSMA-V) [Sivakumar et al 2005, Griffin et al 2014, Cortese et al 2020, Lin et al 2020] -
Uncertain significance, no assertion criteria providedliterature onlyInherited Neuropathy Consortium Ii, University Of MiamiApr 20, 2019- -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 13, 2019The p.H472R variant (also known as c.1415A>G), located in coding exon 11 of the GARS gene, results from an A to G substitution at nucleotide position 1415. The histidine at codon 472 is replaced by arginine, an amino acid with highly similar properties. This variant (also referred to as p.H418R) has been reported in multiple patients with distal hereditary motor neuropathy (also called distal spinal muscular atrophy) and has been shown to segregate with disease (Sivakumar K et al. Brain, 2005 Oct;128:2304-14; Schabhüttl M et al. J. Neurol., 2014 May;261:970-82; Karakaya M et al. Hum. Mutat., 2018 09;39:1284-1298). Functional studies of this alteration demonstrate reduced aminoacylation activity, substantial reductions in yeast viability, and altered cellular localization in transfected mouse motor neuron cell lines (Griffin LB et al. Hum. Mutat., 2014 Nov;35:1363-71; Antonellis A et al. J. Neurosci., 2006 Oct;26:10397-406). In addition to the clinical data presented in the literature, this alteration is absent in population-based cohorts in the Genome Aggregation Database (gnomAD) and predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 08, 2023This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 472 of the GARS protein (p.His472Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with peripheral neuropathy (PMID: 16014653, 24627108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410314). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GARS protein function. Experimental studies have shown that this missense change affects GARS function (PMID: 25168514). For these reasons, this variant has been classified as Pathogenic. -
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, no assertion criteria providedliterature onlyInherited Neuropathy Consortium-- -
Distal spinal muscular atrophy Uncertain:1
Uncertain significance, no assertion criteria providedliterature onlyInherited Neuropathy Consortium-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-7.3
D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.96
MutPred
0.94
Gain of solvent accessibility (P = 0.0584);
MVP
0.97
MPC
1.2
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.97
gMVP
0.94

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: rs1060502838; hg19: chr7-30661064; API