7-30633785-A-G

Position:

• chr7-30633785-A-G

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.2145A>G​(p.Thr715Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0399 in 1,608,902 control chromosomes in the GnomAD database, including 2,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (1155 hom., cov: 31)
  • Exomes 𝑓: 0.035 (1684 hom.)
• Consequence: GARS1 NM_002047.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.72

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=-0.65).
• BP6: Variant 7-30633785-A-G is Benign according to our data. Variant chr7-30633785-A-G is described in ClinVar as [Benign]. Clinvar id is 137443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30633785-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.2145A>G	p.Thr715Thr	synonymous_variant	17/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1983A>G	p.Thr661Thr	synonymous_variant	17/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.2145A>G	p.Thr715Thr	synonymous_variant	17/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.2163A>G	p.Thr721Thr	synonymous_variant	17/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.2043A>G	p.Thr681Thr	synonymous_variant	16/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1977A>G	p.Thr659Thr	synonymous_variant	18/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1944A>G	p.Thr648Thr	synonymous_variant	17/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1776A>G	p.Thr592Thr	synonymous_variant	17/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1776A>G	p.Thr592Thr	synonymous_variant	18/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*566A>G		non_coding_transcript_exon_variant	18/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1859A>G		non_coding_transcript_exon_variant	18/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*1950A>G		non_coding_transcript_exon_variant	17/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1483A>G		non_coding_transcript_exon_variant	18/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*418A>G		non_coding_transcript_exon_variant	16/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*2015A>G		non_coding_transcript_exon_variant	18/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*324A>G		non_coding_transcript_exon_variant	15/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*2087A>G		non_coding_transcript_exon_variant	19/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*1090A>G		non_coding_transcript_exon_variant	17/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1596A>G		non_coding_transcript_exon_variant	17/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1434A>G		non_coding_transcript_exon_variant	18/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1577A>G		non_coding_transcript_exon_variant	17/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.*230A>G		non_coding_transcript_exon_variant	16/16			ENSP00000502681.1
GARS1	ENST00000444666.6	n.*566A>G		3_prime_UTR_variant	18/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1859A>G		3_prime_UTR_variant	18/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*1950A>G		3_prime_UTR_variant	17/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1483A>G		3_prime_UTR_variant	18/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*418A>G		3_prime_UTR_variant	16/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*2015A>G		3_prime_UTR_variant	18/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*324A>G		3_prime_UTR_variant	15/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*2087A>G		3_prime_UTR_variant	19/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*1090A>G		3_prime_UTR_variant	17/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1596A>G		3_prime_UTR_variant	17/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1434A>G		3_prime_UTR_variant	18/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1577A>G		3_prime_UTR_variant	17/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.*230A>G		3_prime_UTR_variant	16/16			ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.0842 AC: 12779 AN: 151840 Hom.: 1146 Cov.: 31

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0512

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.00479

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0680

GnomAD3 exomes AF: 0.0362 AC: 9044 AN: 249520 Hom.: 524 AF XY: 0.0329 AC XY: 4453 AN XY: 135374

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0280

Gnomad ASJ exome AF: 0.0255

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.00778

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0318

Gnomad OTH exome AF: 0.0340

GnomAD4 exome AF: 0.0353 AC: 51393 AN: 1456946 Hom.: 1684 Cov.: 42 AF XY: 0.0340 AC XY: 24607 AN XY: 724742

Gnomad4 AFR exome AF: 0.234

Gnomad4 AMR exome AF: 0.0317

Gnomad4 ASJ exome AF: 0.0243

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.00831

Gnomad4 FIN exome AF: 0.0140

Gnomad4 NFE exome AF: 0.0335

Gnomad4 OTH exome AF: 0.0443

GnomAD4 genome AF: 0.0844 AC: 12819 AN: 151956 Hom.: 1155 Cov.: 31 AF XY: 0.0820 AC XY: 6090 AN XY: 74292

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.0510

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.00501

Gnomad4 FIN AF: 0.0123

Gnomad4 NFE AF: 0.0325

Gnomad4 OTH AF: 0.0673

Alfa AF: 0.0366 Hom.: 106

Bravo AF: 0.0945

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.0358

EpiControl AF: 0.0337

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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 13, 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 29, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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	-0.65
CADD	Benign	0.57
DANN	Benign	0.70

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: rs4593; hg19: chr7-30673401; COSMIC: COSV66828907; COSMIC: COSV66828907;