rs113958280

Variant names:

• chr7-30621453-C-A
• rs113958280
• NM_002047.4:c.1420C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-30621453-C-A
• chr7-30621453-C-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.1420C>A​(p.Arg474Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 1,614,092 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: GARS1 NM_002047.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.389

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=-0.45).
• BP6: Variant 7-30621453-C-A is Benign according to our data. Variant chr7-30621453-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 360013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.389 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.002 (304/152228) while in subpopulation AFR AF= 0.00693 (288/41540). AF 95% confidence interval is 0.00627. There are 3 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 304 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1420C>A	p.Arg474Arg	synonymous_variant	Exon 11 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1258C>A	p.Arg420Arg	synonymous_variant	Exon 11 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1420C>A	p.Arg474Arg	synonymous_variant	Exon 11 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1420C>A	p.Arg474Arg	synonymous_variant	Exon 11 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1318C>A	p.Arg440Arg	synonymous_variant	Exon 10 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1252C>A	p.Arg418Arg	synonymous_variant	Exon 12 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1219C>A	p.Arg407Arg	synonymous_variant	Exon 11 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1051C>A	p.Arg351Arg	synonymous_variant	Exon 11 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1051C>A	p.Arg351Arg	synonymous_variant	Exon 12 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1420C>A		non_coding_transcript_exon_variant	Exon 11 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1134C>A		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*520C>A		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*758C>A		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1420C>A		non_coding_transcript_exon_variant	Exon 11 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1290C>A		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1420C>A		non_coding_transcript_exon_variant	Exon 11 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1362C>A		non_coding_transcript_exon_variant	Exon 13 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*365C>A		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*871C>A		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*709C>A		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*852C>A		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1420C>A		non_coding_transcript_exon_variant	Exon 11 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*1134C>A		3_prime_UTR_variant	Exon 12 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*520C>A		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*758C>A		3_prime_UTR_variant	Exon 12 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*1290C>A		3_prime_UTR_variant	Exon 12 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1362C>A		3_prime_UTR_variant	Exon 13 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*365C>A		3_prime_UTR_variant	Exon 11 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*871C>A		3_prime_UTR_variant	Exon 11 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*709C>A		3_prime_UTR_variant	Exon 12 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*852C>A		3_prime_UTR_variant	Exon 11 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152110 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00686

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000373 AC: 93 AN: 249568 Hom.: 0 AF XY: 0.000266 AC XY: 36 AN XY: 135404

Gnomad AFR exome AF: 0.00497

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000185 AC: 271 AN: 1461864 Hom.: 1 Cov.: 31 AF XY: 0.000142 AC XY: 103 AN XY: 727234

Gnomad4 AFR exome AF: 0.00609

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152228 Hom.: 3 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74414

Gnomad4 AFR AF: 0.00693

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000802 Hom.: 0

Bravo AF: 0.00201

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -

Mar 11, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Aug 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 06, 2020

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. -

Charcot-Marie-Tooth disease type 2 Benign:1

Jan 06, 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
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.8
DANN	Benign	0.63
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: rs113958280; hg19: chr7-30661069;