7-30631471-T-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.1833T>C(p.Val611=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,613,064 control chromosomes in the GnomAD database, including 912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (169 hom., cov: 32)
  • Exomes 𝑓: 0.030 (743 hom.)
• Consequence: GARS1 NM_002047.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.932

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-30631471-T-C is Benign according to our data. Variant chr7-30631471-T-C is described in ClinVar as [Benign]. Clinvar id is 137442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30631471-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.932 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GARS1	NM_002047.4	c.1833T>C	p.Val611=	synonymous_variant	15/17	ENST00000389266.8
GARS1	NM_001316772.1	c.1671T>C	p.Val557=	synonymous_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GARS1	ENST00000389266.8	c.1833T>C	p.Val611=	synonymous_variant	15/17	1	NM_002047.4	P2

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6033 AN: 152196 Hom.: 165 Cov.: 32

Gnomad AFR AF: 0.0696

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0317

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0249 AC: 6193 AN: 249142 Hom.: 125 AF XY: 0.0244 AC XY: 3298 AN XY: 135232

Gnomad AFR exome AF: 0.0681

Gnomad AMR exome AF: 0.0199

Gnomad ASJ exome AF: 0.0255

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00736

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0312

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0300 AC: 43884 AN: 1460750 Hom.: 743 Cov.: 30 AF XY: 0.0294 AC XY: 21381 AN XY: 726706

Gnomad4 AFR exome AF: 0.0722

Gnomad4 AMR exome AF: 0.0222

Gnomad4 ASJ exome AF: 0.0239

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00758

Gnomad4 FIN exome AF: 0.0138

Gnomad4 NFE exome AF: 0.0327

Gnomad4 OTH exome AF: 0.0322

GnomAD4 genome AF: 0.0397 AC: 6048 AN: 152314 Hom.: 169 Cov.: 32 AF XY: 0.0382 AC XY: 2848 AN XY: 74470

Gnomad4 AFR AF: 0.0697

Gnomad4 AMR AF: 0.0343

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0123

Gnomad4 NFE AF: 0.0317

Gnomad4 OTH AF: 0.0326

Alfa AF: 0.0341 Hom.: 99

Bravo AF: 0.0434

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0350

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, 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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 08, 2017	- -

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

Invitae

Feb 01, 2024

- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	3.9
Dann	Benign	0.62
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: rs14270; hg19: chr7-30671087; COSMIC: COSV66828208; COSMIC: COSV66828208;