7-30616026-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_002047.4(GARS1):c.1162C>G(p.Arg388Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R388W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.97

Publications

3 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33107355).

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1162C>G	p.Arg388Gly	missense_variant	Exon 9 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.1000C>G	p.Arg334Gly	missense_variant	Exon 9 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GARS1	ENST00000389266.8 link	c.1162C>G	p.Arg388Gly	missense_variant	Exon 9 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.1162C>G	p.Arg388Gly	missense_variant	Exon 9 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.1060C>G	p.Arg354Gly	missense_variant	Exon 8 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.994C>G	p.Arg332Gly	missense_variant	Exon 10 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.961C>G	p.Arg321Gly	missense_variant	Exon 9 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.793C>G	p.Arg265Gly	missense_variant	Exon 9 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.793C>G	p.Arg265Gly	missense_variant	Exon 10 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.1162C>G		non_coding_transcript_exon_variant	Exon 9 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*876C>G		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*262C>G		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*500C>G		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.1162C>G		non_coding_transcript_exon_variant	Exon 9 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*1032C>G		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.1162C>G		non_coding_transcript_exon_variant	Exon 9 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*1104C>G		non_coding_transcript_exon_variant	Exon 11 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*107C>G		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*613C>G		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*451C>G		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*594C>G		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.1162C>G		non_coding_transcript_exon_variant	Exon 9 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1 link	n.*876C>G		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*262C>G		3_prime_UTR_variant	Exon 10 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*500C>G		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1 link	n.*1032C>G		3_prime_UTR_variant	Exon 10 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*1104C>G		3_prime_UTR_variant	Exon 11 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*107C>G		3_prime_UTR_variant	Exon 9 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*613C>G		3_prime_UTR_variant	Exon 9 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*451C>G		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*594C>G		3_prime_UTR_variant	Exon 9 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000802

AC:

AN:

249522

AF XY:

0.00

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

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:

0.00000809

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.00000657

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R388G variant (also known as c.1162C>G), located in coding exon 9 of the GARS gene, results from a C to G substitution at nucleotide position 1162. The arginine at codon 388 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Charcot-Marie-Tooth disease type 2

Uncertain:1

Apr 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 388 of the GARS protein (p.Arg388Gly). This variant is present in population databases (rs759277467, gnomAD 0.002%). 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: 965772). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

M_CAP

Benign

0.049

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.67

PhyloP100

4.0

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.33

Sift

Benign

0.30

Sift4G

Benign

0.37

Vest4

0.42

ClinPred

0.42

GERP RS

3.4

Varity_R

0.60

gMVP

0.55

Mutation Taster

=70/30

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over