rs187937286

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.699C>T(p.Val233Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,613,772 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

GARS1
NM_002047.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.302

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=-0.38).

BP6

Variant 7-30603536-C-T is Benign according to our data. Variant chr7-30603536-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 360004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.302 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000598 (91/152198) while in subpopulation AFR AF = 0.00176 (73/41540). AF 95% confidence interval is 0.00143. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.699C>T	p.Val233Val	synonymous_variant	Exon 6 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.537C>T	p.Val179Val	synonymous_variant	Exon 6 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GARS1	ENST00000389266.8 link	c.699C>T	p.Val233Val	synonymous_variant	Exon 6 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.699C>T	p.Val233Val	synonymous_variant	Exon 6 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.597C>T	p.Val199Val	synonymous_variant	Exon 5 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.531C>T	p.Val177Val	synonymous_variant	Exon 7 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.498C>T	p.Val166Val	synonymous_variant	Exon 6 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.330C>T	p.Val110Val	synonymous_variant	Exon 6 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.330C>T	p.Val110Val	synonymous_variant	Exon 7 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*413C>T		non_coding_transcript_exon_variant	Exon 7 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*569C>T		non_coding_transcript_exon_variant	Exon 7 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*569C>T		non_coding_transcript_exon_variant	Exon 7 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*150C>T		non_coding_transcript_exon_variant	Exon 6 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*131C>T		non_coding_transcript_exon_variant	Exon 6 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1 link	n.*413C>T		3_prime_UTR_variant	Exon 7 of 18			ENSP00000502408.1
GARS1	ENST00000675529.1 link	n.*569C>T		3_prime_UTR_variant	Exon 7 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*569C>T		3_prime_UTR_variant	Exon 7 of 19			ENSP00000501884.1
GARS1	ENST00000676164.1 link	n.*150C>T		3_prime_UTR_variant	Exon 6 of 17			ENSP00000501986.1
GARS1	ENST00000676259.1 link	n.*131C>T		3_prime_UTR_variant	Exon 6 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes

AF:

0.000605

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000188

AC:

AN:

249416

AF XY:

0.000126

show subpopulations

Gnomad AFR exome

AF:

0.00226

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000739

AC:

108

AN:

1461574

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.00218

AC:

AN:

33474

American (AMR)

AF:

0.000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111896

Other (OTH)

AF:

0.000149

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.000598

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

41540

American (AMR)

AF:

0.000915

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67994

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000442

Hom.:

Bravo

AF:

0.000831

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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.

Feb 17, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Apr 26, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GARS1: BP4, BP7, BS1

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

Apr 25, 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 12, 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

-0.38

CADD

Benign

9.2

(source)

DANN

Benign

0.65

PhyloP100

0.30

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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