rs11553502

Positions:

• chr7-30615926-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002047.4(GARS1):​c.1062T>C​(p.Phe354=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0311 in 1,614,144 control chromosomes in the GnomAD database, including 913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (166 hom., cov: 33)
  • Exomes 𝑓: 0.030 (747 hom.)
• Consequence: GARS1 NM_002047.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 5.07

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 (BayesDel_noAF=-0.53).
• BP6: Variant 7-30615926-T-C is Benign according to our data. Variant chr7-30615926-T-C is described in ClinVar as [Benign]. Clinvar id is 137440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30615926-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1062T>C	p.Phe354=	synonymous_variant	9/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.900T>C	p.Phe300=	synonymous_variant	9/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1062T>C	p.Phe354=	synonymous_variant	9/17	1	NM_002047.4	ENSP00000373918	P2

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6030 AN: 152176 Hom.: 162 Cov.: 33

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0318

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0249 AC: 6209 AN: 249552 Hom.: 127 AF XY: 0.0244 AC XY: 3305 AN XY: 135394

Gnomad AFR exome AF: 0.0680

Gnomad AMR exome AF: 0.0199

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00735

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0312

Gnomad OTH exome AF: 0.0272

GnomAD4 exome AF: 0.0302 AC: 44205 AN: 1461850 Hom.: 747 Cov.: 32 AF XY: 0.0296 AC XY: 21520 AN XY: 727230

Gnomad4 AFR exome AF: 0.0725

Gnomad4 AMR exome AF: 0.0223

Gnomad4 ASJ exome AF: 0.0240

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00762

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.0329

Gnomad4 OTH exome AF: 0.0324

GnomAD4 genome AF: 0.0397 AC: 6044 AN: 152294 Hom.: 166 Cov.: 33 AF XY: 0.0383 AC XY: 2852 AN XY: 74474

Gnomad4 AFR AF: 0.0696

Gnomad4 AMR AF: 0.0343

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.0318

Gnomad4 OTH AF: 0.0326

Alfa AF: 0.0346 Hom.: 155

Bravo AF: 0.0433

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0349

EpiControl AF: 0.0330

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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 03, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 01, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -

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

- -

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	-0.53
CADD	Benign	10
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11553502; hg19: chr7-30655542;