chr7-30631471-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002047.4(GARS1):c.1833T>C(p.Val611Val) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.932

Publications

6 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 2D
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
neuronopathy, distal hereditary motor, type 5A
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Laboratory for Molecular Medicine
spinal muscular atrophy, infantile, James type
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

GARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 137442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1833T>C	p.Val611Val	synonymous_variant	Exon 15 of 17	ENST00000389266.8	NP_002038.2	P41250-1
GARS1	NM_001316772.1 link	c.1671T>C	p.Val557Val	synonymous_variant	Exon 15 of 17		NP_001303701.1	P41250-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GARS1	ENST00000389266.8 link	c.1833T>C	p.Val611Val	synonymous_variant	Exon 15 of 17	1	NM_002047.4	ENSP00000373918.3	P41250-1
GARS1	ENST00000675651.1 link	c.1833T>C	p.Val611Val	synonymous_variant	Exon 15 of 17			ENSP00000502513.1	A0A6Q8PGZ8
GARS1	ENST00000675810.1 link	c.1731T>C	p.Val577Val	synonymous_variant	Exon 14 of 16			ENSP00000502743.1	A0A6Q8PHH9
GARS1	ENST00000675693.1 link	c.1665T>C	p.Val555Val	synonymous_variant	Exon 16 of 18			ENSP00000502174.1	A0A6Q8PGA8
GARS1	ENST00000675051.1 link	c.1632T>C	p.Val544Val	synonymous_variant	Exon 15 of 17			ENSP00000502296.1	A0A6Q8PGI6
GARS1	ENST00000674815.1 link	c.1464T>C	p.Val488Val	synonymous_variant	Exon 15 of 17			ENSP00000502799.1	A0A6Q8PGW4
GARS1	ENST00000674851.1 link	c.1464T>C	p.Val488Val	synonymous_variant	Exon 16 of 18			ENSP00000502451.1	A0A6Q8PGW4
GARS1	ENST00000444666.6 link	n.*254T>C		non_coding_transcript_exon_variant	Exon 16 of 18	3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 link	n.*1547T>C		non_coding_transcript_exon_variant	Exon 16 of 18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 link	n.*933T>C		non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 link	n.*1171T>C		non_coding_transcript_exon_variant	Exon 16 of 18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000674807.1 link	n.*106T>C		non_coding_transcript_exon_variant	Exon 14 of 16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 link	n.*1703T>C		non_coding_transcript_exon_variant	Exon 16 of 18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000676088.1 link	n.*1775T>C		non_coding_transcript_exon_variant	Exon 17 of 19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 link	n.*778T>C		non_coding_transcript_exon_variant	Exon 15 of 17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 link	n.*1284T>C		non_coding_transcript_exon_variant	Exon 15 of 17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 link	n.*1122T>C		non_coding_transcript_exon_variant	Exon 16 of 18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 link	n.*1265T>C		non_coding_transcript_exon_variant	Exon 15 of 17			ENSP00000501980.1	A0A6Q8PFU7
GARS1	ENST00000444666.6 link	n.*254T>C		3_prime_UTR_variant	Exon 16 of 18	3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 link	n.*1547T>C		3_prime_UTR_variant	Exon 16 of 18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 link	n.*933T>C		3_prime_UTR_variant	Exon 16 of 17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 link	n.*1171T>C		3_prime_UTR_variant	Exon 16 of 18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000674807.1 link	n.*106T>C		3_prime_UTR_variant	Exon 14 of 16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 link	n.*1703T>C		3_prime_UTR_variant	Exon 16 of 18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000676088.1 link	n.*1775T>C		3_prime_UTR_variant	Exon 17 of 19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 link	n.*778T>C		3_prime_UTR_variant	Exon 15 of 17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 link	n.*1284T>C		3_prime_UTR_variant	Exon 15 of 17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 link	n.*1122T>C		3_prime_UTR_variant	Exon 16 of 18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 link	n.*1265T>C		3_prime_UTR_variant	Exon 15 of 17			ENSP00000501980.1	A0A6Q8PFU7
GARS1	ENST00000675859.1 link	n.*83-776T>C		intron_variant	Intron 13 of 14			ENSP00000502033.1	A0A6Q8PFZ6
GARS1	ENST00000676403.1 link	n.1810-776T>C		intron_variant	Intron 14 of 15			ENSP00000502681.1	A0A6Q8PHI7

Frequencies

GnomAD3 genomes

AF:

0.0396

AC:

6033

AN:

152196

Hom.:

165

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0249

AC:

6193

AN:

249142

AF XY:

0.0244

show subpopulations

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 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.:

AF XY:

0.0294

AC XY:

21381

AN XY:

726706

show subpopulations

African (AFR)

AF:

0.0722

AC:

2414

AN:

33440

American (AMR)

AF:

0.0222

AC:

994

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0239

AC:

624

AN:

26120

East Asian (EAS)

AF:

0.000101

AC:

AN:

39668

South Asian (SAS)

AF:

0.00758

AC:

654

AN:

86250

European-Finnish (FIN)

AF:

0.0138

AC:

738

AN:

53376

Middle Eastern (MID)

AF:

0.0314

AC:

181

AN:

5764

European-Non Finnish (NFE)

AF:

0.0327

AC:

36331

AN:

1111066

Other (OTH)

AF:

0.0322

AC:

1944

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

1939

3878

5816

7755

9694

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1364

2728

4092

5456

6820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0397

AC:

6048

AN:

152314

Hom.:

169

Cov.:

AF XY:

0.0382

AC XY:

2848

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0697

AC:

2897

AN:

41562

American (AMR)

AF:

0.0343

AC:

524

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00477

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0123

AC:

130

AN:

10612

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0317

AC:

2160

AN:

68042

Other (OTH)

AF:

0.0326

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

293

586

878

1171

1464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0359

Hom.:

129

Bravo

AF:

0.0434

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0350

EpiControl

AF:

0.0330

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 03, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 29, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 08, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Distal spinal muscular atrophy

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 2D

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Neuronopathy, distal hereditary motor, type 5A

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.9

(source)

DANN

Benign

0.62

PhyloP100

-0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over