rs200279483

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002047.4(GARS1):c.408A>C(p.Gln136His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q136K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.22

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.408A>C	p.Gln136His	missense_variant	Exon 3 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.246A>C	p.Gln82His	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.408A>C	p.Gln136His	missense_variant	Exon 3 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.408A>C	p.Gln136His	missense_variant	Exon 3 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.306A>C	p.Gln102His	missense_variant	Exon 2 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.240A>C	p.Gln80His	missense_variant	Exon 4 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.207A>C	p.Gln69His	missense_variant	Exon 3 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.39A>C	p.Gln13His	missense_variant	Exon 3 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.39A>C	p.Gln13His	missense_variant	Exon 4 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.408A>C		non_coding_transcript_exon_variant	Exon 3 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*122A>C		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.408A>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.408A>C		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.408A>C		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*278A>C		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.408A>C		non_coding_transcript_exon_variant	Exon 3 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*278A>C		non_coding_transcript_exon_variant	Exon 4 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.408A>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.408A>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.408A>C		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.408A>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.408A>C		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1 link	n.*122A>C		3_prime_UTR_variant	Exon 4 of 18			ENSP00000502408.1
GARS1	ENST00000675529.1 link	n.*278A>C		3_prime_UTR_variant	Exon 4 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*278A>C		3_prime_UTR_variant	Exon 4 of 19			ENSP00000501884.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460620

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726746

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110870

Other (OTH)

AF:

0.00

AC:

AN:

60360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.42

PhyloP100

1.2

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.61

Sift

Benign

0.14

Sift4G

Uncertain

0.027

Polyphen

0.37

Vest4

0.77

MutPred

0.69

Loss of helix (P = 0.3949);

MVP

0.91

MPC

0.93

ClinPred

0.98

GERP RS

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.79

Mutation Taster

=36/64

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over