rs187937286

Variant names:

• chr7-30603536-C-T
• rs187937286
• NM_002047.4:c.699C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.302

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• 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	c.699C>T	p.Val233Val	synonymous_variant	Exon 6 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	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	Appris	UniProt
GARS1	ENST00000389266.8	c.699C>T	p.Val233Val	synonymous_variant	Exon 6 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.699C>T	p.Val233Val	synonymous_variant	Exon 6 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.597C>T	p.Val199Val	synonymous_variant	Exon 5 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.531C>T	p.Val177Val	synonymous_variant	Exon 7 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.498C>T	p.Val166Val	synonymous_variant	Exon 6 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.330C>T	p.Val110Val	synonymous_variant	Exon 6 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.330C>T	p.Val110Val	synonymous_variant	Exon 7 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*413C>T		non_coding_transcript_exon_variant	Exon 7 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*569C>T		non_coding_transcript_exon_variant	Exon 7 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*569C>T		non_coding_transcript_exon_variant	Exon 7 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*150C>T		non_coding_transcript_exon_variant	Exon 6 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*131C>T		non_coding_transcript_exon_variant	Exon 6 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.699C>T		non_coding_transcript_exon_variant	Exon 6 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*413C>T		3_prime_UTR_variant	Exon 7 of 18			ENSP00000502408.1
GARS1	ENST00000675529.1	n.*569C>T		3_prime_UTR_variant	Exon 7 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*569C>T		3_prime_UTR_variant	Exon 7 of 19			ENSP00000501884.1
GARS1	ENST00000676164.1	n.*150C>T		3_prime_UTR_variant	Exon 6 of 17			ENSP00000501986.1
GARS1	ENST00000676259.1	n.*131C>T		3_prime_UTR_variant	Exon 6 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152082 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000188 AC: 47 AN: 249416 Hom.: 0 AF XY: 0.000126 AC XY: 17 AN XY: 135332

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 SAS exome AF: 0.0000327

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.: 0 Cov.: 31 AF XY: 0.0000688 AC XY: 50 AN XY: 727102

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74394

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000442 Hom.: 0

Bravo AF: 0.000831

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 17, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:2

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 -

Apr 26, 2018

GeneDx

Significance: Likely 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

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

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
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.2
DANN	Benign	0.65
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

LitVar

Other links and lift over

dbSNP: rs187937286; hg19: chr7-30643152; COSMIC: COSV66828002; COSMIC: COSV66828002;