NM_002047.4:c.1171C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_002047.4(GARS1):c.1171C>T(p.Arg391Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R391H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3598734).

BP6

Variant 7-30616035-C-T is Benign according to our data. Variant chr7-30616035-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447371.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000198 (29/1461854) while in subpopulation MID AF = 0.000174 (1/5758). AF 95% confidence interval is 0.000013. There are 0 homozygotes in GnomAdExome4. There are 17 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1171C>T	p.Arg391Cys	missense_variant	Exon 9 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.1009C>T	p.Arg337Cys	missense_variant	Exon 9 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GARS1	ENST00000389266.8 link	c.1171C>T	p.Arg391Cys	missense_variant	Exon 9 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.1171C>T	p.Arg391Cys	missense_variant	Exon 9 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.1069C>T	p.Arg357Cys	missense_variant	Exon 8 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.1003C>T	p.Arg335Cys	missense_variant	Exon 10 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.970C>T	p.Arg324Cys	missense_variant	Exon 9 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.802C>T	p.Arg268Cys	missense_variant	Exon 9 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.802C>T	p.Arg268Cys	missense_variant	Exon 10 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.1171C>T		non_coding_transcript_exon_variant	Exon 9 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*885C>T		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*271C>T		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*509C>T		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.1171C>T		non_coding_transcript_exon_variant	Exon 9 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*1041C>T		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.1171C>T		non_coding_transcript_exon_variant	Exon 9 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*1113C>T		non_coding_transcript_exon_variant	Exon 11 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*116C>T		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*622C>T		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*460C>T		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*603C>T		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.1171C>T		non_coding_transcript_exon_variant	Exon 9 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1 link	n.*885C>T		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*271C>T		3_prime_UTR_variant	Exon 10 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*509C>T		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1 link	n.*1041C>T		3_prime_UTR_variant	Exon 10 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*1113C>T		3_prime_UTR_variant	Exon 11 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*116C>T		3_prime_UTR_variant	Exon 9 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*622C>T		3_prime_UTR_variant	Exon 9 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*460C>T		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*603C>T		3_prime_UTR_variant	Exon 9 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD2 exomes

AF:

0.0000281

AC:

AN:

249502

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

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:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111988

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.0000131

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41438

American (AMR)

AF:

0.0000655

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:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Uncertain:1Benign:1

Inherited Neuropathy Consortium

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 14, 2019

Genesis Genome Database

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Uncertain:1Benign:1

Apr 07, 2021

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 22, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26752306, 24078732) -

not specified

Uncertain:1

May 04, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R391C variant (also known as c.1171C>T), located in coding exon 9 of the GARS gene, results from a C to T substitution at nucleotide position 1171. The arginine at codon 391 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in an individual with Charcot-Marie-Tooth (CMT) disease, and in an unaffected control individual in a different CMT disease cohort; however, clinical details were limited (Sivera R et al. Neurology, 2013 Oct;81:1617-25; Lupo V et al. J Mol Diagn, 2016 Mar;18:225-34). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 2

Uncertain:1

Jun 04, 2022

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 cysteine, which is neutral and slightly polar, at codon 391 of the GARS protein (p.Arg391Cys). This variant is present in population databases (rs370057212, gnomAD 0.003%). This missense change has been observed in individual(s) with Charcot Marie Tooth disease (PMID: 24078732). ClinVar contains an entry for this variant (Variation ID: 447371). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Charcot-Marie-Tooth disease type 2D

Uncertain:1

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

Eigen

Benign

-0.031

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.055

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.55

PhyloP100

4.8

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.50

Sift

Benign

0.12

Sift4G

Uncertain

0.043

Polyphen

0.056

Vest4

0.50

MutPred

0.58

Loss of disorder (P = 0.0042);

MVP

0.93

MPC

1.2

ClinPred

0.20

GERP RS

5.2

Varity_R

0.38

gMVP

0.72

Mutation Taster

=26/74

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over