rs370650205

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_ModerateBS1_SupportingBS2

The NM_002047.4(GARS1):c.1219G>A(p.Gly407Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

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

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O: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: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.907

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000394 (6/152138) while in subpopulation NFE AF = 0.0000588 (4/68032). AF 95% confidence interval is 0.0000197. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1219G>A	p.Gly407Ser	missense_variant	Exon 10 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.1057G>A	p.Gly353Ser	missense_variant	Exon 10 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GARS1	ENST00000389266.8 link	c.1219G>A	p.Gly407Ser	missense_variant	Exon 10 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.1219G>A	p.Gly407Ser	missense_variant	Exon 10 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.1117G>A	p.Gly373Ser	missense_variant	Exon 9 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.1051G>A	p.Gly351Ser	missense_variant	Exon 11 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.1018G>A	p.Gly340Ser	missense_variant	Exon 10 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.850G>A	p.Gly284Ser	missense_variant	Exon 10 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.850G>A	p.Gly284Ser	missense_variant	Exon 11 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.1219G>A		non_coding_transcript_exon_variant	Exon 10 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*933G>A		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*319G>A		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*557G>A		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.1219G>A		non_coding_transcript_exon_variant	Exon 10 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*1089G>A		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.1219G>A		non_coding_transcript_exon_variant	Exon 10 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*1161G>A		non_coding_transcript_exon_variant	Exon 12 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*164G>A		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*670G>A		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*508G>A		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*651G>A		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.1219G>A		non_coding_transcript_exon_variant	Exon 10 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1 link	n.*933G>A		3_prime_UTR_variant	Exon 11 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*319G>A		3_prime_UTR_variant	Exon 11 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*557G>A		3_prime_UTR_variant	Exon 11 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1 link	n.*1089G>A		3_prime_UTR_variant	Exon 11 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*1161G>A		3_prime_UTR_variant	Exon 12 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*164G>A		3_prime_UTR_variant	Exon 10 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*670G>A		3_prime_UTR_variant	Exon 10 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*508G>A		3_prime_UTR_variant	Exon 11 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*651G>A		3_prime_UTR_variant	Exon 10 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

249548

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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:

152138

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000683

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 19, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G407S variant (also known as c.1219G>A), located in coding exon 10 of the GARS gene, results from a G to A substitution at nucleotide position 1219. The glycine at codon 407 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Charcot-Marie-Tooth disease type 2

Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 407 of the GARS protein (p.Gly407Ser). This variant is present in population databases (rs370650205, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with GARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 577910). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GARS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Charcot-Marie-Tooth disease type 2D;CN031873:Neuronopathy, distal hereditary motor, type 5A;CN118836:GARS-Associated Axonal Neuropathy

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 04-13-2020 by Invitae. GenomeConnect-InvitaePIN assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.80

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.13

PhyloP100

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.8

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Vest4

0.91

ClinPred

0.95

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.76

Mutation Taster

=13/87

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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