rs2230310

Variant names:

• chr7-30609652-C-T
• rs2230310
• NM_002047.4:c.803C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002047.4(GARS1):​c.803C>T​(p.Thr268Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00393 in 1,613,140 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T268T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (19 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 6.04
• Publications: 15 publications found

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_002047.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011372536).
• BP6: Variant 7-30609652-C-T is Benign according to our data. Variant chr7-30609652-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 188100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00352 (536/152290) while in subpopulation NFE AF = 0.00546 (371/68004). AF 95% confidence interval is 0.005. There are 2 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 536 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.803C>T	p.Thr268Ile	missense_variant	Exon 7 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.641C>T	p.Thr214Ile	missense_variant	Exon 7 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.803C>T	p.Thr268Ile	missense_variant	Exon 7 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.803C>T	p.Thr268Ile	missense_variant	Exon 7 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.701C>T	p.Thr234Ile	missense_variant	Exon 6 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.635C>T	p.Thr212Ile	missense_variant	Exon 8 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.602C>T	p.Thr201Ile	missense_variant	Exon 7 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.434C>T	p.Thr145Ile	missense_variant	Exon 7 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.434C>T	p.Thr145Ile	missense_variant	Exon 8 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.803C>T		non_coding_transcript_exon_variant	Exon 7 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*517C>T		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.803C>T		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*141C>T		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.803C>T		non_coding_transcript_exon_variant	Exon 7 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*673C>T		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.803C>T		non_coding_transcript_exon_variant	Exon 7 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*745C>T		non_coding_transcript_exon_variant	Exon 9 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.803C>T		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*254C>T		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*92C>T		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*235C>T		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.803C>T		non_coding_transcript_exon_variant	Exon 7 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*517C>T		3_prime_UTR_variant	Exon 8 of 18			ENSP00000502408.1
GARS1	ENST00000674737.1	n.*141C>T		3_prime_UTR_variant	Exon 8 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*673C>T		3_prime_UTR_variant	Exon 8 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*745C>T		3_prime_UTR_variant	Exon 9 of 19			ENSP00000501884.1
GARS1	ENST00000676164.1	n.*254C>T		3_prime_UTR_variant	Exon 7 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*92C>T		3_prime_UTR_variant	Exon 8 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*235C>T		3_prime_UTR_variant	Exon 7 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 536 AN: 152172 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00545

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00344 AC: 857 AN: 249452 AF XY: 0.00330

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00745

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00492

Gnomad NFE exome AF: 0.00503

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00397 AC: 5805 AN: 1460850 Hom.: 19 Cov.: 30 AF XY: 0.00403 AC XY: 2929 AN XY: 726828

African (AFR) AF: 0.000628 AC: 21 AN: 33446

American (AMR) AF: 0.00186 AC: 83 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00716 AC: 187 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86230

European-Finnish (FIN) AF: 0.00436 AC: 233 AN: 53398

Middle Eastern (MID) AF: 0.00781 AC: 45 AN: 5764

European-Non Finnish (NFE) AF: 0.00441 AC: 4903 AN: 1111198

Other (OTH) AF: 0.00461 AC: 278 AN: 60356

GnomAD4 genome AF: 0.00352 AC: 536 AN: 152290 Hom.: 2 Cov.: 33 AF XY: 0.00310 AC XY: 231 AN XY: 74474

African (AFR) AF: 0.000770 AC: 32 AN: 41566

American (AMR) AF: 0.00366 AC: 56 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00546 AC: 371 AN: 68004

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00354 Hom.: 10

Bravo AF: 0.00342

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00109 AC: 4

ESP6500EA AF: 0.00651 AC: 53

ExAC AF: 0.00317 AC: 383

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00573

EpiControl AF: 0.00533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:9

Mar 11, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GARS1: BS1 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 13, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32028661, 29520015, 28594869, 27582484) -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

Feb 02, 2022

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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 31, 2015

Eurofins Ntd Llc (ga)

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. -

Charcot-Marie-Tooth disease type 2 Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GARS1-related disorder Benign:1

Oct 17, 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 2D 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. -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.049	D
PhyloP100		6.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.66	P
Vest4		0.48
MVP		0.66
MPC		0.99
ClinPred		0.11	T
GERP RS		4.9
Varity_R		0.48
gMVP		0.65
Mutation Taster		=23/77	disease causing

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

Other links and lift over

dbSNP: rs2230310; hg19: chr7-30649268;