rs750971084

Variant names:

Variant summary

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

The NM_002047.4(GARS1):c.1534G>A(p.Ala512Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.96

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 7-30622383-G-A is Benign according to our data. Variant chr7-30622383-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 543209.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000394 (6/152182) while in subpopulation AMR AF = 0.000393 (6/15274). AF 95% confidence interval is 0.00017. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1534G>A	p.Ala512Thr	missense_variant	Exon 12 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.1372G>A	p.Ala458Thr	missense_variant	Exon 12 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GARS1	ENST00000389266.8 link	c.1534G>A	p.Ala512Thr	missense_variant	Exon 12 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.1534G>A	p.Ala512Thr	missense_variant	Exon 12 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.1432G>A	p.Ala478Thr	missense_variant	Exon 11 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.1366G>A	p.Ala456Thr	missense_variant	Exon 13 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.1333G>A	p.Ala445Thr	missense_variant	Exon 12 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.1165G>A	p.Ala389Thr	missense_variant	Exon 12 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.1165G>A	p.Ala389Thr	missense_variant	Exon 13 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.1534G>A		non_coding_transcript_exon_variant	Exon 12 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*1248G>A		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*634G>A		non_coding_transcript_exon_variant	Exon 13 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*872G>A		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.1534G>A		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*1404G>A		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.1534G>A		non_coding_transcript_exon_variant	Exon 12 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*1476G>A		non_coding_transcript_exon_variant	Exon 14 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*479G>A		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*985G>A		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*823G>A		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*966G>A		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.1534G>A		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1 link	n.*1248G>A		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*634G>A		3_prime_UTR_variant	Exon 13 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*872G>A		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1 link	n.*1404G>A		3_prime_UTR_variant	Exon 13 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*1476G>A		3_prime_UTR_variant	Exon 14 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*479G>A		3_prime_UTR_variant	Exon 12 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*985G>A		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*823G>A		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*966G>A		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000521

AC:

AN:

249558

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000348

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:

0.000165

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000335

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:

86256

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:

1111976

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

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:

0.0000394

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.000393

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000282

Hom.:

Bravo

AF:

0.0000340

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

Jul 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1534G>A (p.A512T) alteration is located in exon 12 (coding exon 12) of the GARS gene. This alteration results from a G to A substitution at nucleotide position 1534, causing the alanine (A) at amino acid position 512 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Charcot-Marie-Tooth disease type 2

Benign:1

Jan 13, 2025

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

0.17

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

0.19

PhyloP100

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.57

Sift

Benign

0.045

Sift4G

Uncertain

0.040

Vest4

0.75

ClinPred

0.57

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.63

Mutation Taster

=19/81

disease causing

(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