rs17159287

Variant names:

• chr7-30616027-G-A
• rs17159287
• NM_002047.4:c.1163G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002047.4(GARS1):​c.1163G>A​(p.Arg388Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,614,150 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (14 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.06

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050005615).
• BP6: Variant 7-30616027-G-A is Benign according to our data. Variant chr7-30616027-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 360012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00778 (1185/152266) while in subpopulation AFR AF= 0.0267 (1110/41548). AF 95% confidence interval is 0.0254. There are 14 homozygotes in gnomad4. There are 537 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1185 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1163G>A	p.Arg388Gln	missense_variant	Exon 9 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1001G>A	p.Arg334Gln	missense_variant	Exon 9 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1163G>A	p.Arg388Gln	missense_variant	Exon 9 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1163G>A	p.Arg388Gln	missense_variant	Exon 9 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1061G>A	p.Arg354Gln	missense_variant	Exon 8 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.995G>A	p.Arg332Gln	missense_variant	Exon 10 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.962G>A	p.Arg321Gln	missense_variant	Exon 9 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.794G>A	p.Arg265Gln	missense_variant	Exon 9 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.794G>A	p.Arg265Gln	missense_variant	Exon 10 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1163G>A		non_coding_transcript_exon_variant	Exon 9 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*877G>A		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*263G>A		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*501G>A		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1163G>A		non_coding_transcript_exon_variant	Exon 9 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1033G>A		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1163G>A		non_coding_transcript_exon_variant	Exon 9 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1105G>A		non_coding_transcript_exon_variant	Exon 11 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*108G>A		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*614G>A		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*452G>A		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*595G>A		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1163G>A		non_coding_transcript_exon_variant	Exon 9 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*877G>A		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*263G>A		3_prime_UTR_variant	Exon 10 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*501G>A		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*1033G>A		3_prime_UTR_variant	Exon 10 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1105G>A		3_prime_UTR_variant	Exon 11 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*108G>A		3_prime_UTR_variant	Exon 9 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*614G>A		3_prime_UTR_variant	Exon 9 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*452G>A		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*595G>A		3_prime_UTR_variant	Exon 9 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.00781 AC: 1188 AN: 152148 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00219 AC: 546 AN: 249512 Hom.: 8 AF XY: 0.00167 AC XY: 226 AN XY: 135384

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.000935 AC: 1367 AN: 1461884 Hom.: 14 Cov.: 31 AF XY: 0.000813 AC XY: 591 AN XY: 727244

Gnomad4 AFR exome AF: 0.0284

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00778 AC: 1185 AN: 152266 Hom.: 14 Cov.: 33 AF XY: 0.00721 AC XY: 537 AN XY: 74466

Gnomad4 AFR AF: 0.0267

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00164 Hom.: 5

Bravo AF: 0.00841

ESP6500AA AF: 0.0213 AC: 82

ESP6500EA AF: 0.000363 AC: 3

ExAC AF: 0.00257 AC: 311

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GARS1: BP4, BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 11, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 06, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 17, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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 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: 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	Benign	0.055
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.14
Sift	Benign	0.86	T
Sift4G	Benign	0.65	T
Polyphen		0.0020	B
Vest4		0.070
MVP		0.53
MPC		0.40
ClinPred		0.018	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.20
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs17159287; hg19: chr7-30655643;