7-30595014-G-C

Position:

• chr7-30595014-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002047.4(GARS1):​c.93G>C​(p.Leu31Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0986 in 1,580,278 control chromosomes in the GnomAD database, including 8,756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (875 hom., cov: 33)
  • Exomes 𝑓: 0.098 (7881 hom.)
• Consequence: GARS1 NM_002047.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.670

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-30595014-G-C is Benign according to our data. Variant chr7-30595014-G-C is described in ClinVar as [Benign]. Clinvar id is 137444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30595014-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.93G>C	p.Leu31Leu	synonymous_variant	1/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.-70G>C		5_prime_UTR_variant	1/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.93G>C	p.Leu31Leu	synonymous_variant	1/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.93G>C	p.Leu31Leu	synonymous_variant	1/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.93G>C	p.Leu31Leu	synonymous_variant	1/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.18+75G>C		intron_variant				ENSP00000502174.1
GARS1	ENST00000675051.1	c.22-3782G>C		intron_variant				ENSP00000502296.1
GARS1	ENST00000674815.1	c.-148+62G>C		intron_variant				ENSP00000502799.1
GARS1	ENST00000674851.1	c.-184+62G>C		intron_variant				ENSP00000502451.1
GARS1	ENST00000444666.6	n.93G>C		non_coding_transcript_exon_variant	1/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.93G>C		non_coding_transcript_exon_variant	1/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.93G>C		non_coding_transcript_exon_variant	1/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.93G>C		non_coding_transcript_exon_variant	1/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.93G>C		non_coding_transcript_exon_variant	1/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.93G>C		non_coding_transcript_exon_variant	1/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.93G>C		non_coding_transcript_exon_variant	1/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.93G>C		non_coding_transcript_exon_variant	1/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.93G>C		non_coding_transcript_exon_variant	1/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.93G>C		non_coding_transcript_exon_variant	1/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.93G>C		non_coding_transcript_exon_variant	1/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.93G>C		non_coding_transcript_exon_variant	1/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.93G>C		non_coding_transcript_exon_variant	1/16			ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15532 AN: 152104 Hom.: 873 Cov.: 33

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0935

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0878

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.111 AC: 21591 AN: 194036 Hom.: 1377 AF XY: 0.115 AC XY: 12363 AN XY: 107414

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.0752

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.161

Gnomad SAS exome AF: 0.192

Gnomad FIN exome AF: 0.0635

Gnomad NFE exome AF: 0.0936

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.0982 AC: 140215 AN: 1428056 Hom.: 7881 Cov.: 31 AF XY: 0.101 AC XY: 71417 AN XY: 709156

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.0768

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.191

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.0626

Gnomad4 NFE exome AF: 0.0884

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.102 AC: 15542 AN: 152222 Hom.: 875 Cov.: 33 AF XY: 0.103 AC XY: 7653 AN XY: 74432

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0934

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.179

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.0612

Gnomad4 NFE AF: 0.0877

Gnomad4 OTH AF: 0.132

Alfa AF: 0.0656 Hom.: 119

Bravo AF: 0.106

Asia WGS AF: 0.212 AC: 737 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2021	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Distal spinal muscular atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 15, 2016

- -

Charcot-Marie-Tooth disease type 2D Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.81
CADD	Benign	3.1
DANN	Benign	0.58

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: rs2529438; hg19: chr7-30634630; COSMIC: COSV66828729; COSMIC: COSV66828729;