rs773316961

Positions:

chr7-30631455-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_002047.4(GARS1):c.1817G>A(p.Ser606Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.59

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:

GARS1 (HGNC:):

GARS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37260664).

BP6

Variant 7-30631455-G-A is Benign according to our data. Variant chr7-30631455-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 543238.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4 linkuse as main transcript	c.1817G>A	p.Ser606Asn	missense_variant	15/17	ENST00000389266.8	NP_002038.2	P41250-1
GARS1	NM_001316772.1 linkuse as main transcript	c.1655G>A	p.Ser552Asn	missense_variant	15/17		NP_001303701.1	P41250-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GARS1	ENST00000389266.8 linkuse as main transcript	c.1817G>A	p.Ser606Asn	missense_variant	15/17	1	NM_002047.4	ENSP00000373918.3	P41250-1
GARS1	ENST00000675651.1 linkuse as main transcript	c.1817G>A	p.Ser606Asn	missense_variant	15/17			ENSP00000502513.1	A0A6Q8PGZ8
GARS1	ENST00000675810.1 linkuse as main transcript	c.1715G>A	p.Ser572Asn	missense_variant	14/16			ENSP00000502743.1	A0A6Q8PHH9
GARS1	ENST00000675693.1 linkuse as main transcript	c.1649G>A	p.Ser550Asn	missense_variant	16/18			ENSP00000502174.1	A0A6Q8PGA8
GARS1	ENST00000675051.1 linkuse as main transcript	c.1616G>A	p.Ser539Asn	missense_variant	15/17			ENSP00000502296.1	A0A6Q8PGI6
GARS1	ENST00000674815.1 linkuse as main transcript	c.1448G>A	p.Ser483Asn	missense_variant	15/17			ENSP00000502799.1	A0A6Q8PGW4
GARS1	ENST00000674851.1 linkuse as main transcript	c.1448G>A	p.Ser483Asn	missense_variant	16/18			ENSP00000502451.1	A0A6Q8PGW4
GARS1	ENST00000444666.6 linkuse as main transcript	n.*238G>A		non_coding_transcript_exon_variant	16/18	3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 linkuse as main transcript	n.*1531G>A		non_coding_transcript_exon_variant	16/18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 linkuse as main transcript	n.*917G>A		non_coding_transcript_exon_variant	16/17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 linkuse as main transcript	n.*1155G>A		non_coding_transcript_exon_variant	16/18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000674807.1 linkuse as main transcript	n.*90G>A		non_coding_transcript_exon_variant	14/16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 linkuse as main transcript	n.*1687G>A		non_coding_transcript_exon_variant	16/18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000676088.1 linkuse as main transcript	n.*1759G>A		non_coding_transcript_exon_variant	17/19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 linkuse as main transcript	n.*762G>A		non_coding_transcript_exon_variant	15/17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 linkuse as main transcript	n.*1268G>A		non_coding_transcript_exon_variant	15/17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 linkuse as main transcript	n.*1106G>A		non_coding_transcript_exon_variant	16/18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 linkuse as main transcript	n.*1249G>A		non_coding_transcript_exon_variant	15/17			ENSP00000501980.1	A0A6Q8PFU7
GARS1	ENST00000444666.6 linkuse as main transcript	n.*238G>A		3_prime_UTR_variant	16/18	3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 linkuse as main transcript	n.*1531G>A		3_prime_UTR_variant	16/18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 linkuse as main transcript	n.*917G>A		3_prime_UTR_variant	16/17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 linkuse as main transcript	n.*1155G>A		3_prime_UTR_variant	16/18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000674807.1 linkuse as main transcript	n.*90G>A		3_prime_UTR_variant	14/16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 linkuse as main transcript	n.*1687G>A		3_prime_UTR_variant	16/18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000676088.1 linkuse as main transcript	n.*1759G>A		3_prime_UTR_variant	17/19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 linkuse as main transcript	n.*762G>A		3_prime_UTR_variant	15/17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 linkuse as main transcript	n.*1268G>A		3_prime_UTR_variant	15/17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 linkuse as main transcript	n.*1106G>A		3_prime_UTR_variant	16/18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 linkuse as main transcript	n.*1249G>A		3_prime_UTR_variant	15/17			ENSP00000501980.1	A0A6Q8PFU7
GARS1	ENST00000675859.1 linkuse as main transcript	n.*83-792G>A		intron_variant				ENSP00000502033.1	A0A6Q8PFZ6
GARS1	ENST00000676403.1 linkuse as main transcript	n.1810-792G>A		intron_variant				ENSP00000502681.1	A0A6Q8PHI7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

248980

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000620

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1460496

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726650

show subpopulations

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:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

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

Sep 20, 2022

This variant has not been reported in the literature in individuals affected with GARS-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GARS protein function. ClinVar contains an entry for this variant (Variation ID: 543238). This variant is present in population databases (rs773316961, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 606 of the GARS protein (p.Ser606Asn). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

GARS1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.020

MetaRNN

Benign

0.37

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.1

REVEL

Benign

0.18

Sift

Benign

0.050

Sift4G

Uncertain

0.044

Polyphen

0.27

Vest4

0.51

MutPred

0.50

Loss of disorder (P = 0.1176);

MVP

0.59

MPC

0.58

ClinPred

0.52

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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