7-30626280-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_002047.4(GARS1):c.1660G>T(p.Asp554Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,778 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. D554N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.70

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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-30626280-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9208.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1660G>T	p.Asp554Tyr	missense_variant	Exon 13 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.1498G>T	p.Asp500Tyr	missense_variant	Exon 13 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GARS1	ENST00000389266.8 link	c.1660G>T	p.Asp554Tyr	missense_variant	Exon 13 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.1660G>T	p.Asp554Tyr	missense_variant	Exon 13 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.1558G>T	p.Asp520Tyr	missense_variant	Exon 12 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.1492G>T	p.Asp498Tyr	missense_variant	Exon 14 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.1459G>T	p.Asp487Tyr	missense_variant	Exon 13 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.1291G>T	p.Asp431Tyr	missense_variant	Exon 13 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.1291G>T	p.Asp431Tyr	missense_variant	Exon 14 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.1660G>T		non_coding_transcript_exon_variant	Exon 13 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*1374G>T		non_coding_transcript_exon_variant	Exon 14 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*760G>T		non_coding_transcript_exon_variant	Exon 14 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*998G>T		non_coding_transcript_exon_variant	Exon 14 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1 link	n.*1530G>T		non_coding_transcript_exon_variant	Exon 14 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*1602G>T		non_coding_transcript_exon_variant	Exon 15 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*605G>T		non_coding_transcript_exon_variant	Exon 13 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*1111G>T		non_coding_transcript_exon_variant	Exon 13 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*949G>T		non_coding_transcript_exon_variant	Exon 14 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*1092G>T		non_coding_transcript_exon_variant	Exon 13 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.1660G>T		non_coding_transcript_exon_variant	Exon 13 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1 link	n.*1374G>T		3_prime_UTR_variant	Exon 14 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*760G>T		3_prime_UTR_variant	Exon 14 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*998G>T		3_prime_UTR_variant	Exon 14 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1 link	n.*1530G>T		3_prime_UTR_variant	Exon 14 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*1602G>T		3_prime_UTR_variant	Exon 15 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*605G>T		3_prime_UTR_variant	Exon 13 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*1111G>T		3_prime_UTR_variant	Exon 13 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*949G>T		3_prime_UTR_variant	Exon 14 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*1092G>T		3_prime_UTR_variant	Exon 13 of 17			ENSP00000501980.1
GARS1	ENST00000674807.1 link	n.1614-2280G>T		intron_variant	Intron 12 of 15			ENSP00000502814.1
GARS1	ENST00000675859.1 link	n.1614-2280G>T		intron_variant	Intron 12 of 14			ENSP00000502033.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455778

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724682

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33362

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.00

AC:

AN:

86054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106618

Other (OTH)

AF:

0.00

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Benign

0.24

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.62

PhyloP100

7.7

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.015

Polyphen

0.65

Vest4

0.76

MutPred

0.52

Gain of MoRF binding (P = 0.0455);

MVP

0.92

MPC

1.1

ClinPred

1.0

GERP RS

5.5

Varity_R

0.79

gMVP

0.77

Mutation Taster

=11/89

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Computational scores

Splicing

Publications

Other links and lift over