rs370057212

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002047.4(GARS1):c.1171C>A(p.Arg391Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.80

Publications

2 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1171C>A	p.Arg391Ser	missense_variant	Exon 9 of 17	ENST00000389266.8	NP_002038.2	P41250-1
GARS1	NM_001316772.1 link	c.1009C>A	p.Arg337Ser	missense_variant	Exon 9 of 17		NP_001303701.1	P41250-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GARS1	ENST00000389266.8 link	c.1171C>A	p.Arg391Ser	missense_variant	Exon 9 of 17	1	NM_002047.4	ENSP00000373918.3	P41250-1
GARS1	ENST00000675651.1 link	c.1171C>A	p.Arg391Ser	missense_variant	Exon 9 of 17			ENSP00000502513.1	A0A6Q8PGZ8
GARS1	ENST00000675810.1 link	c.1069C>A	p.Arg357Ser	missense_variant	Exon 8 of 16			ENSP00000502743.1	A0A6Q8PHH9
GARS1	ENST00000675693.1 link	c.1003C>A	p.Arg335Ser	missense_variant	Exon 10 of 18			ENSP00000502174.1	A0A6Q8PGA8
GARS1	ENST00000675051.1 link	c.970C>A	p.Arg324Ser	missense_variant	Exon 9 of 17			ENSP00000502296.1	A0A6Q8PGI6
GARS1	ENST00000674815.1 link	c.802C>A	p.Arg268Ser	missense_variant	Exon 9 of 17			ENSP00000502799.1	A0A6Q8PGW4
GARS1	ENST00000674851.1 link	c.802C>A	p.Arg268Ser	missense_variant	Exon 10 of 18			ENSP00000502451.1	A0A6Q8PGW4
GARS1	ENST00000444666.6 link	n.1171C>A		non_coding_transcript_exon_variant	Exon 9 of 18	3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 link	n.*885C>A		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 link	n.*271C>A		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 link	n.*509C>A		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000674807.1 link	n.1171C>A		non_coding_transcript_exon_variant	Exon 9 of 16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 link	n.*1041C>A		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000675859.1 link	n.1171C>A		non_coding_transcript_exon_variant	Exon 9 of 15			ENSP00000502033.1	A0A6Q8PFZ6
GARS1	ENST00000676088.1 link	n.*1113C>A		non_coding_transcript_exon_variant	Exon 11 of 19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 link	n.*116C>A		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 link	n.*622C>A		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 link	n.*460C>A		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 link	n.*603C>A		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000501980.1	A0A6Q8PFU7
GARS1	ENST00000676403.1 link	n.1171C>A		non_coding_transcript_exon_variant	Exon 9 of 16			ENSP00000502681.1	A0A6Q8PHI7
GARS1	ENST00000674616.1 link	n.*885C>A		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 link	n.*271C>A		3_prime_UTR_variant	Exon 10 of 17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 link	n.*509C>A		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000675529.1 link	n.*1041C>A		3_prime_UTR_variant	Exon 10 of 18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000676088.1 link	n.*1113C>A		3_prime_UTR_variant	Exon 11 of 19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 link	n.*116C>A		3_prime_UTR_variant	Exon 9 of 17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 link	n.*622C>A		3_prime_UTR_variant	Exon 9 of 17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 link	n.*460C>A		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 link	n.*603C>A		3_prime_UTR_variant	Exon 9 of 17			ENSP00000501980.1	A0A6Q8PFU7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

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

GnomAD2 exomes

AF:

0.00000802

AC:

AN:

249502

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111988

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 15, 2023

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.1171C>A (p.Arg391Ser) results in a non-conservative amino acid change located in the aminoacyl-tRNA synthetase, class II domain (IPR006195) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function.The variant allele was found at a frequency of 8e-06 in 249502 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1171C>A in individuals affected with GARS1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Charcot-Marie-Tooth disease type 2

Uncertain:1

Jun 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 391 of the GARS protein (p.Arg391Ser). This variant is present in population databases (rs370057212, gnomAD 0.003%). This missense change has been observed in individual(s) with GARS-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 1053030). 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 with a negative predictive value of 95%. 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. -

not provided

Uncertain:1

Mar 30, 2022

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.089

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.054

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.77

PhyloP100

4.8

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.010

REVEL

Uncertain

0.33

Sift

Benign

0.80

Sift4G

Benign

0.38

Polyphen

0.020

Vest4

0.72

MVP

0.92

MPC

0.44

ClinPred

0.53

GERP RS

5.2

Varity_R

0.55

gMVP

0.68

Mutation Taster

=25/75

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over