rs189589556

Positions:

• chr7-30612259-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002047.4(GARS1):​c.1031+14T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,612,824 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (19 hom.)
• Consequence: GARS1 NM_002047.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.32

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 -16 ACMG points.

• BP6: Variant 7-30612259-T-G is Benign according to our data. Variant chr7-30612259-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 258530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30612259-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00213 (325/152362) while in subpopulation NFE AF= 0.00375 (255/68028). AF 95% confidence interval is 0.00337. There are 1 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 325 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1031+14T>G		intron_variant		ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.869+14T>G		intron_variant			NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1031+14T>G		intron_variant		1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1031+14T>G		intron_variant				ENSP00000502513.1
GARS1	ENST00000675810.1	c.929+14T>G		intron_variant				ENSP00000502743.1
GARS1	ENST00000675693.1	c.863+14T>G		intron_variant				ENSP00000502174.1
GARS1	ENST00000675051.1	c.830+14T>G		intron_variant				ENSP00000502296.1
GARS1	ENST00000674815.1	c.662+14T>G		intron_variant				ENSP00000502799.1
GARS1	ENST00000674851.1	c.662+14T>G		intron_variant				ENSP00000502451.1
GARS1	ENST00000444666.6	n.1031+14T>G		intron_variant		3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*745+14T>G		intron_variant				ENSP00000502408.1
GARS1	ENST00000674643.1	n.1031+14T>G		intron_variant				ENSP00000501636.1
GARS1	ENST00000674737.1	n.*369+14T>G		intron_variant				ENSP00000502464.1
GARS1	ENST00000674807.1	n.1031+14T>G		intron_variant				ENSP00000502814.1
GARS1	ENST00000675529.1	n.*901+14T>G		intron_variant				ENSP00000501655.1
GARS1	ENST00000675859.1	n.1031+14T>G		intron_variant				ENSP00000502033.1
GARS1	ENST00000676088.1	n.*973+14T>G		intron_variant				ENSP00000501884.1
GARS1	ENST00000676140.1	n.1031+14T>G		intron_variant				ENSP00000502571.1
GARS1	ENST00000676164.1	n.*482+14T>G		intron_variant				ENSP00000501986.1
GARS1	ENST00000676210.1	n.*320+14T>G		intron_variant				ENSP00000502373.1
GARS1	ENST00000676259.1	n.*463+14T>G		intron_variant				ENSP00000501980.1
GARS1	ENST00000676403.1	n.1031+14T>G		intron_variant				ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 325 AN: 152244 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00175 AC: 437 AN: 249478 Hom.: 2 AF XY: 0.00171 AC XY: 231 AN XY: 135374

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.000882

Gnomad NFE exome AF: 0.00296

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00332 AC: 4846 AN: 1460462 Hom.: 19 Cov.: 31 AF XY: 0.00320 AC XY: 2324 AN XY: 726638

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00201

Gnomad4 FIN exome AF: 0.000861

Gnomad4 NFE exome AF: 0.00394

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.00213 AC: 325 AN: 152362 Hom.: 1 Cov.: 33 AF XY: 0.00196 AC XY: 146 AN XY: 74506

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00273 Hom.: 0

Bravo AF: 0.00215

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2015	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	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	GARS1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 09, 2019	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

Charcot-Marie-Tooth disease Benign:1

Likely 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

Jan 29, 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	-0.74
CADD	Benign	13
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.74		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs189589556; hg19: chr7-30651875;