rs888805042

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002047.4(GARS1):c.418A>C(p.Ile140Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I140V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.29

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.418A>C	p.Ile140Leu	missense_variant	Exon 3 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.256A>C	p.Ile86Leu	missense_variant	Exon 3 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GARS1	ENST00000389266.8 link	c.418A>C	p.Ile140Leu	missense_variant	Exon 3 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.418A>C	p.Ile140Leu	missense_variant	Exon 3 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.316A>C	p.Ile106Leu	missense_variant	Exon 2 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.250A>C	p.Ile84Leu	missense_variant	Exon 4 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.217A>C	p.Ile73Leu	missense_variant	Exon 3 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.49A>C	p.Ile17Leu	missense_variant	Exon 3 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.49A>C	p.Ile17Leu	missense_variant	Exon 4 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*132A>C		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*288A>C		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*288A>C		non_coding_transcript_exon_variant	Exon 4 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1 link	n.*132A>C		3_prime_UTR_variant	Exon 4 of 18			ENSP00000502408.1
GARS1	ENST00000675529.1 link	n.*288A>C		3_prime_UTR_variant	Exon 4 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*288A>C		3_prime_UTR_variant	Exon 4 of 19			ENSP00000501884.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1457510

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725420

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33404

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

86166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1108072

Other (OTH)

AF:

0.00

AC:

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2

Uncertain:1

Sep 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine with leucine at codon 140 of the GARS protein (p.Ile140Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with GARS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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

0.31

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.29

PhyloP100

9.3

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.65

Sift

Uncertain

0.027

Sift4G

Benign

0.063

Vest4

0.77

ClinPred

0.81

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.75

Mutation Taster

=37/63

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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