7-30617138-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002047.4(GARS1):c.1219G>C(p.Gly407Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 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. G407S) 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: 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1219G>C	p.Gly407Arg	missense_variant	Exon 10 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.1057G>C	p.Gly353Arg	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>C	p.Gly407Arg	missense_variant	Exon 10 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.1219G>C	p.Gly407Arg	missense_variant	Exon 10 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.1117G>C	p.Gly373Arg	missense_variant	Exon 9 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.1051G>C	p.Gly351Arg	missense_variant	Exon 11 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.1018G>C	p.Gly340Arg	missense_variant	Exon 10 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.850G>C	p.Gly284Arg	missense_variant	Exon 10 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.850G>C	p.Gly284Arg	missense_variant	Exon 11 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.1219G>C		non_coding_transcript_exon_variant	Exon 10 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*933G>C		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*319G>C		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*557G>C		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.1219G>C		non_coding_transcript_exon_variant	Exon 10 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*1089G>C		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.1219G>C		non_coding_transcript_exon_variant	Exon 10 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*1161G>C		non_coding_transcript_exon_variant	Exon 12 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*164G>C		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*670G>C		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*508G>C		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*651G>C		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.1219G>C		non_coding_transcript_exon_variant	Exon 10 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1 link	n.*933G>C		3_prime_UTR_variant	Exon 11 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*319G>C		3_prime_UTR_variant	Exon 11 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*557G>C		3_prime_UTR_variant	Exon 11 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1 link	n.*1089G>C		3_prime_UTR_variant	Exon 11 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*1161G>C		3_prime_UTR_variant	Exon 12 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*164G>C		3_prime_UTR_variant	Exon 10 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*670G>C		3_prime_UTR_variant	Exon 10 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*508G>C		3_prime_UTR_variant	Exon 11 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*651G>C		3_prime_UTR_variant	Exon 10 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

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:

8.99e-7

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.11

PhyloP100

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.97

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.92

Mutation Taster

=5/95

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 39

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

Computational scores

Splicing

Publications

Other links and lift over