rs754547488

Positions:

chr7-30628589-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002047.4(GARS1):c.1729C>A(p.Pro577Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.88

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1729C>A	p.Pro577Thr	missense_variant	14/17	ENST00000389266.8	NP_002038.2	P41250-1
GARS1	NM_001316772.1 link	c.1567C>A	p.Pro523Thr	missense_variant	14/17		NP_001303701.1	P41250-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GARS1	ENST00000389266.8 link	c.1729C>A	p.Pro577Thr	missense_variant	14/17	1	NM_002047.4	ENSP00000373918.3	P41250-1
GARS1	ENST00000675651.1 link	c.1729C>A	p.Pro577Thr	missense_variant	14/17			ENSP00000502513.1	A0A6Q8PGZ8
GARS1	ENST00000675810.1 link	c.1627C>A	p.Pro543Thr	missense_variant	13/16			ENSP00000502743.1	A0A6Q8PHH9
GARS1	ENST00000675693.1 link	c.1561C>A	p.Pro521Thr	missense_variant	15/18			ENSP00000502174.1	A0A6Q8PGA8
GARS1	ENST00000675051.1 link	c.1528C>A	p.Pro510Thr	missense_variant	14/17			ENSP00000502296.1	A0A6Q8PGI6
GARS1	ENST00000674815.1 link	c.1360C>A	p.Pro454Thr	missense_variant	14/17			ENSP00000502799.1	A0A6Q8PGW4
GARS1	ENST00000674851.1 link	c.1360C>A	p.Pro454Thr	missense_variant	15/18			ENSP00000502451.1	A0A6Q8PGW4
GARS1	ENST00000444666.6 link	n.*150C>A		non_coding_transcript_exon_variant	15/18	3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 link	n.*1443C>A		non_coding_transcript_exon_variant	15/18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 link	n.*829C>A		non_coding_transcript_exon_variant	15/17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 link	n.*1067C>A		non_coding_transcript_exon_variant	15/18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000674807.1 link	n.*2C>A		non_coding_transcript_exon_variant	13/16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 link	n.*1599C>A		non_coding_transcript_exon_variant	15/18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000675859.1 link	n.*2C>A		non_coding_transcript_exon_variant	13/15			ENSP00000502033.1	A0A6Q8PFZ6
GARS1	ENST00000676088.1 link	n.*1671C>A		non_coding_transcript_exon_variant	16/19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 link	n.*674C>A		non_coding_transcript_exon_variant	14/17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 link	n.*1180C>A		non_coding_transcript_exon_variant	14/17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 link	n.*1018C>A		non_coding_transcript_exon_variant	15/18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 link	n.*1161C>A		non_coding_transcript_exon_variant	14/17			ENSP00000501980.1	A0A6Q8PFU7
GARS1	ENST00000676403.1 link	n.1729C>A		non_coding_transcript_exon_variant	14/16			ENSP00000502681.1	A0A6Q8PHI7
GARS1	ENST00000444666.6 link	n.*150C>A		3_prime_UTR_variant	15/18	3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 link	n.*1443C>A		3_prime_UTR_variant	15/18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 link	n.*829C>A		3_prime_UTR_variant	15/17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 link	n.*1067C>A		3_prime_UTR_variant	15/18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000674807.1 link	n.*2C>A		3_prime_UTR_variant	13/16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 link	n.*1599C>A		3_prime_UTR_variant	15/18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000675859.1 link	n.*2C>A		3_prime_UTR_variant	13/15			ENSP00000502033.1	A0A6Q8PFZ6
GARS1	ENST00000676088.1 link	n.*1671C>A		3_prime_UTR_variant	16/19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 link	n.*674C>A		3_prime_UTR_variant	14/17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 link	n.*1180C>A		3_prime_UTR_variant	14/17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 link	n.*1018C>A		3_prime_UTR_variant	15/18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 link	n.*1161C>A		3_prime_UTR_variant	14/17			ENSP00000501980.1	A0A6Q8PFU7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726448

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2024

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 577 of the GARS protein (p.Pro577Thr). This variant is not present in population databases (gnomAD no frequency). 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: 579111). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GARS protein function with a positive predictive value of 95%. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 18, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26503042, 26138142, 25168514) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.92

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.93

MutPred

0.90

Gain of sheet (P = 0.1208);

MVP

0.93

MPC

1.2

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.81

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over