rs750971084

Positions:

chr7-30622383-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_002047.4(GARS1):c.1534G>A(p.Ala512Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.96

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 Benign. Variant got -9 ACMG points.

BP6

Variant 7-30622383-G-A is Benign according to our data. Variant chr7-30622383-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 543209.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000394 (6/152182) while in subpopulation AMR AF= 0.000393 (6/15274). AF 95% confidence interval is 0.00017. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4 linkuse as main transcript	c.1534G>A	p.Ala512Thr	missense_variant	12/17	ENST00000389266.8	NP_002038.2	P41250-1
GARS1	NM_001316772.1 linkuse as main transcript	c.1372G>A	p.Ala458Thr	missense_variant	12/17		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.1534G>A	p.Ala512Thr	missense_variant	12/17	1	NM_002047.4	ENSP00000373918.3	P41250-1
GARS1	ENST00000675651.1 linkuse as main transcript	c.1534G>A	p.Ala512Thr	missense_variant	12/17			ENSP00000502513.1	A0A6Q8PGZ8
GARS1	ENST00000675810.1 linkuse as main transcript	c.1432G>A	p.Ala478Thr	missense_variant	11/16			ENSP00000502743.1	A0A6Q8PHH9
GARS1	ENST00000675693.1 linkuse as main transcript	c.1366G>A	p.Ala456Thr	missense_variant	13/18			ENSP00000502174.1	A0A6Q8PGA8
GARS1	ENST00000675051.1 linkuse as main transcript	c.1333G>A	p.Ala445Thr	missense_variant	12/17			ENSP00000502296.1	A0A6Q8PGI6
GARS1	ENST00000674815.1 linkuse as main transcript	c.1165G>A	p.Ala389Thr	missense_variant	12/17			ENSP00000502799.1	A0A6Q8PGW4
GARS1	ENST00000674851.1 linkuse as main transcript	c.1165G>A	p.Ala389Thr	missense_variant	13/18			ENSP00000502451.1	A0A6Q8PGW4
GARS1	ENST00000444666.6 linkuse as main transcript	n.1534G>A		non_coding_transcript_exon_variant	12/18	3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 linkuse as main transcript	n.*1248G>A		non_coding_transcript_exon_variant	13/18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 linkuse as main transcript	n.*634G>A		non_coding_transcript_exon_variant	13/17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 linkuse as main transcript	n.*872G>A		non_coding_transcript_exon_variant	13/18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000674807.1 linkuse as main transcript	n.1534G>A		non_coding_transcript_exon_variant	12/16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 linkuse as main transcript	n.*1404G>A		non_coding_transcript_exon_variant	13/18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000675859.1 linkuse as main transcript	n.1534G>A		non_coding_transcript_exon_variant	12/15			ENSP00000502033.1	A0A6Q8PFZ6
GARS1	ENST00000676088.1 linkuse as main transcript	n.*1476G>A		non_coding_transcript_exon_variant	14/19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 linkuse as main transcript	n.*479G>A		non_coding_transcript_exon_variant	12/17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 linkuse as main transcript	n.*985G>A		non_coding_transcript_exon_variant	12/17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 linkuse as main transcript	n.*823G>A		non_coding_transcript_exon_variant	13/18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 linkuse as main transcript	n.*966G>A		non_coding_transcript_exon_variant	12/17			ENSP00000501980.1	A0A6Q8PFU7
GARS1	ENST00000676403.1 linkuse as main transcript	n.1534G>A		non_coding_transcript_exon_variant	12/16			ENSP00000502681.1	A0A6Q8PHI7
GARS1	ENST00000674616.1 linkuse as main transcript	n.*1248G>A		3_prime_UTR_variant	13/18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 linkuse as main transcript	n.*634G>A		3_prime_UTR_variant	13/17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 linkuse as main transcript	n.*872G>A		3_prime_UTR_variant	13/18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000675529.1 linkuse as main transcript	n.*1404G>A		3_prime_UTR_variant	13/18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000676088.1 linkuse as main transcript	n.*1476G>A		3_prime_UTR_variant	14/19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 linkuse as main transcript	n.*479G>A		3_prime_UTR_variant	12/17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 linkuse as main transcript	n.*985G>A		3_prime_UTR_variant	12/17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 linkuse as main transcript	n.*823G>A		3_prime_UTR_variant	13/18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 linkuse as main transcript	n.*966G>A		3_prime_UTR_variant	12/17			ENSP00000501980.1	A0A6Q8PFU7

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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

GnomAD3 exomes

AF:

0.0000521

AC:

AN:

249558

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135392

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000348

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:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000335

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:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000393

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:

0.0000282

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.1534G>A (p.A512T) alteration is located in exon 12 (coding exon 12) of the GARS gene. This alteration results from a G to A substitution at nucleotide position 1534, causing the alanine (A) at amino acid position 512 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

0.19

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.57

Sift

Benign

0.045

Sift4G

Uncertain

0.040

Polyphen

0.074

Vest4

0.75

MutPred

0.44

Gain of helix (P = 0.0199);

MVP

0.88

MPC

1.1

ClinPred

0.57

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.63

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