rs201927627

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_002047.4(GARS1):c.1962C>T(p.Ile654Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,614,132 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

GARS1
NM_002047.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.691

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 7-30632305-C-T is Benign according to our data. Variant chr7-30632305-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 219915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.691 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00127 (193/152262) while in subpopulation SAS AF = 0.00207 (10/4822). AF 95% confidence interval is 0.00155. There are 1 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 193 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1962C>T	p.Ile654Ile	synonymous_variant	Exon 16 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.1800C>T	p.Ile600Ile	synonymous_variant	Exon 16 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GARS1	ENST00000389266.8 link	c.1962C>T	p.Ile654Ile	synonymous_variant	Exon 16 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.1980C>T	p.Ile660Ile	synonymous_variant	Exon 16 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.1860C>T	p.Ile620Ile	synonymous_variant	Exon 15 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.1794C>T	p.Ile598Ile	synonymous_variant	Exon 17 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.1761C>T	p.Ile587Ile	synonymous_variant	Exon 16 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.1593C>T	p.Ile531Ile	synonymous_variant	Exon 16 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.1593C>T	p.Ile531Ile	synonymous_variant	Exon 17 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.*383C>T		non_coding_transcript_exon_variant	Exon 17 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*1676C>T		non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*1767C>T		non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*1300C>T		non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.*235C>T		non_coding_transcript_exon_variant	Exon 15 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*1832C>T		non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.*141C>T		non_coding_transcript_exon_variant	Exon 14 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*1904C>T		non_coding_transcript_exon_variant	Exon 18 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*907C>T		non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*1413C>T		non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*1251C>T		non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*1394C>T		non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.*47C>T		non_coding_transcript_exon_variant	Exon 15 of 16			ENSP00000502681.1
GARS1	ENST00000444666.6 link	n.*383C>T		3_prime_UTR_variant	Exon 17 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*1676C>T		3_prime_UTR_variant	Exon 17 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*1767C>T		3_prime_UTR_variant	Exon 16 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*1300C>T		3_prime_UTR_variant	Exon 17 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.*235C>T		3_prime_UTR_variant	Exon 15 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*1832C>T		3_prime_UTR_variant	Exon 17 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.*141C>T		3_prime_UTR_variant	Exon 14 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*1904C>T		3_prime_UTR_variant	Exon 18 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*907C>T		3_prime_UTR_variant	Exon 16 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*1413C>T		3_prime_UTR_variant	Exon 16 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*1251C>T		3_prime_UTR_variant	Exon 17 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*1394C>T		3_prime_UTR_variant	Exon 16 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.*47C>T		3_prime_UTR_variant	Exon 15 of 16			ENSP00000502681.1

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

193

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00174

AC:

435

AN:

249512

AF XY:

0.00175

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00455

Gnomad NFE exome

AF:

0.00201

Gnomad OTH exome

AF:

0.00280

GnomAD4 exome

AF:

0.00178

AC:

2605

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

1351

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.00152

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00150

AC:

129

AN:

86258

European-Finnish (FIN)

AF:

0.00346

AC:

185

AN:

53418

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00189

AC:

2102

AN:

1111998

Other (OTH)

AF:

0.00179

AC:

108

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

143

286

428

571

714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.00127

AC:

193

AN:

152262

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41556

American (AMR)

AF:

0.00118

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00181

AC:

123

AN:

68014

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00170

Hom.:

Bravo

AF:

0.00137

EpiCase

AF:

0.00147

EpiControl

AF:

0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 15, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GARS1: BP4, BP7

not specified

Benign:2

Jul 11, 2019

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.

Apr 30, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

GARS1-related disorder

Benign:1

Jun 11, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Charcot-Marie-Tooth disease type 2

Benign:1

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

1.9

(source)

DANN

Benign

0.77

PhyloP100

-0.69

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Mutation Taster

=100/0

polymorphism

(source)

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

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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