rs367589841

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_002047.4(GARS1):c.1543G>A(p.Val515Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V515A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.72

Publications

0 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 -9 ACMG points.

BP6

Variant 7-30622392-G-A is Benign according to our data. Variant chr7-30622392-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 577795.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000131 (20/152200) while in subpopulation AFR AF = 0.000482 (20/41454). AF 95% confidence interval is 0.00032. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1543G>A	p.Val515Met	missense_variant	Exon 12 of 17	ENST00000389266.8	NP_002038.2	P41250-1
GARS1	NM_001316772.1 link	c.1381G>A	p.Val461Met	missense_variant	Exon 12 of 17		NP_001303701.1	P41250-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GARS1	ENST00000389266.8 link	c.1543G>A	p.Val515Met	missense_variant	Exon 12 of 17	1	NM_002047.4	ENSP00000373918.3	P41250-1
GARS1	ENST00000675651.1 link	c.1543G>A	p.Val515Met	missense_variant	Exon 12 of 17			ENSP00000502513.1	A0A6Q8PGZ8
GARS1	ENST00000675810.1 link	c.1441G>A	p.Val481Met	missense_variant	Exon 11 of 16			ENSP00000502743.1	A0A6Q8PHH9
GARS1	ENST00000675693.1 link	c.1375G>A	p.Val459Met	missense_variant	Exon 13 of 18			ENSP00000502174.1	A0A6Q8PGA8
GARS1	ENST00000675051.1 link	c.1342G>A	p.Val448Met	missense_variant	Exon 12 of 17			ENSP00000502296.1	A0A6Q8PGI6
GARS1	ENST00000674815.1 link	c.1174G>A	p.Val392Met	missense_variant	Exon 12 of 17			ENSP00000502799.1	A0A6Q8PGW4
GARS1	ENST00000674851.1 link	c.1174G>A	p.Val392Met	missense_variant	Exon 13 of 18			ENSP00000502451.1	A0A6Q8PGW4
GARS1	ENST00000444666.6 link	n.1543G>A		non_coding_transcript_exon_variant	Exon 12 of 18	3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 link	n.*1257G>A		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 link	n.*643G>A		non_coding_transcript_exon_variant	Exon 13 of 17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 link	n.*881G>A		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000674807.1 link	n.1543G>A		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 link	n.*1413G>A		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000675859.1 link	n.1543G>A		non_coding_transcript_exon_variant	Exon 12 of 15			ENSP00000502033.1	A0A6Q8PFZ6
GARS1	ENST00000676088.1 link	n.*1485G>A		non_coding_transcript_exon_variant	Exon 14 of 19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 link	n.*488G>A		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 link	n.*994G>A		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 link	n.*832G>A		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 link	n.*975G>A		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501980.1	A0A6Q8PFU7
GARS1	ENST00000676403.1 link	n.1543G>A		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000502681.1	A0A6Q8PHI7
GARS1	ENST00000674616.1 link	n.*1257G>A		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 link	n.*643G>A		3_prime_UTR_variant	Exon 13 of 17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 link	n.*881G>A		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000675529.1 link	n.*1413G>A		3_prime_UTR_variant	Exon 13 of 18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000676088.1 link	n.*1485G>A		3_prime_UTR_variant	Exon 14 of 19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 link	n.*488G>A		3_prime_UTR_variant	Exon 12 of 17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 link	n.*994G>A		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 link	n.*832G>A		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 link	n.*975G>A		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501980.1	A0A6Q8PFU7

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

249566

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.000387

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000131

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.000482

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000658

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.000257

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 27, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V515M variant (also known as c.1543G>A), located in coding exon 12 of the GARS gene, results from a G to A substitution at nucleotide position 1543. The valine at codon 515 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is unlikely to be causative of Charcot-Marie Tooth type 2D (CMT2D) and distal hereditary motor neuronopathy type VA; however, its contribution to the development of GARS-related mitochondrial respiratory chain dysfunction is uncertain. -

Charcot-Marie-Tooth disease type 2

Benign:1

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.55

MetaSVM

Pathogenic

0.92

PhyloP100

5.7

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.96

Vest4

0.42

MVP

0.83

MPC

0.82

ClinPred

0.84

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.49

Mutation Taster

=71/29

polymorphism

(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