7-30594877-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001316772.1(GARS1):c.-207C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000554 in 1,480,052 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

GARS1
NM_001316772.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.351

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-DT (HGNC:48951): (GARS1 divergent transcript)

GARS1-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000046 (7/152164) while in subpopulation EAS AF = 0.000193 (1/5182). AF 95% confidence interval is 0.0000117. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_001316772.1 link	c.-207C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17		NP_001303701.1	P41250-2
GARS1	NM_001316772.1 link	c.-207C>T	5_prime_UTR_variant	Exon 1 of 17		NP_001303701.1	P41250-2
GARS1	NM_002047.4 link	c.-45C>T	upstream_gene_variant		ENST00000389266.8	NP_002038.2	P41250-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GARS1	ENST00000675810 link	c.-45C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16			ENSP00000502743.1	A0A6Q8PHH9
GARS1	ENST00000674815 link	c.-223C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17			ENSP00000502799.1	A0A6Q8PGW4
GARS1	ENST00000675810 link	c.-45C>T	5_prime_UTR_variant	Exon 1 of 16			ENSP00000502743.1	A0A6Q8PHH9
GARS1	ENST00000674815 link	c.-223C>T	5_prime_UTR_variant	Exon 1 of 17			ENSP00000502799.1	A0A6Q8PGW4
GARS1	ENST00000675051.1 link	c.22-3919C>T	intron_variant	Intron 1 of 16			ENSP00000502296.1	A0A6Q8PGI6
GARS1	ENST00000674643.1 link	n.-45C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674807.1 link	n.-45C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 link	n.-45C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000676088.1 link	n.-45C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676210.1 link	n.-45C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676403.1 link	n.-45C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16			ENSP00000502681.1	A0A6Q8PHI7
GARS1	ENST00000674643.1 link	n.-45C>T	non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674807.1 link	n.-45C>T	non_coding_transcript_exon_variant	Exon 1 of 16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 link	n.-45C>T	non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000676088.1 link	n.-45C>T	non_coding_transcript_exon_variant	Exon 1 of 19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676210.1 link	n.-45C>T	non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676403.1 link	n.-45C>T	non_coding_transcript_exon_variant	Exon 1 of 16			ENSP00000502681.1	A0A6Q8PHI7
GARS1	ENST00000674643.1 link	n.-45C>T	5_prime_UTR_variant	Exon 1 of 17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674807.1 link	n.-45C>T	5_prime_UTR_variant	Exon 1 of 16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 link	n.-45C>T	5_prime_UTR_variant	Exon 1 of 18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000676088.1 link	n.-45C>T	5_prime_UTR_variant	Exon 1 of 19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676210.1 link	n.-45C>T	5_prime_UTR_variant	Exon 1 of 18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676403.1 link	n.-45C>T	5_prime_UTR_variant	Exon 1 of 16			ENSP00000502681.1	A0A6Q8PHI7
GARS1	ENST00000389266.8 link	c.-45C>T	upstream_gene_variant		1	NM_002047.4	ENSP00000373918.3	P41250-1
GARS1	ENST00000675651.1 link	c.-45C>T	upstream_gene_variant				ENSP00000502513.1	A0A6Q8PGZ8
GARS1	ENST00000675693.1 link	c.-45C>T	upstream_gene_variant				ENSP00000502174.1	A0A6Q8PGA8
GARS1	ENST00000674851.1 link	c.-259C>T	upstream_gene_variant				ENSP00000502451.1	A0A6Q8PGW4
GARS1	ENST00000444666.6 link	n.-45C>T	upstream_gene_variant		3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 link	n.-45C>T	upstream_gene_variant				ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674737.1 link	n.-45C>T	upstream_gene_variant				ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000675859.1 link	n.-45C>T	upstream_gene_variant				ENSP00000502033.1	A0A6Q8PFZ6
GARS1	ENST00000676140.1 link	n.-45C>T	upstream_gene_variant				ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 link	n.-45C>T	upstream_gene_variant				ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676259.1 link	n.-45C>T	upstream_gene_variant				ENSP00000501980.1	A0A6Q8PFU7

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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

GnomAD2 exomes

AF:

0.0000395

AC:

AN:

126568

AF XY:

0.0000288

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000565

AC:

AN:

1327888

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

657738

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

29916

Gnomad4 AMR exome

AF:

0.0000569

AC:

AN:

35144

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

24662

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

35066

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

77692

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

34852

Gnomad4 NFE exome

AF:

0.0000698

AC:

AN:

1030782

Gnomad4 Remaining exome

AF:

0.0000179

AC:

AN:

55808

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

AF:

0.0000460

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000483

AC:

0.0000482602

AN:

0.0000482602

Gnomad4 AMR

AF:

0.0000654

AC:

0.0000654193

AN:

0.0000654193

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000193

AC:

0.000192976

AN:

0.000192976

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000441

AC:

0.0000441176

AN:

0.0000441176

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 15, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A variant of uncertain significance has been identified in the GARS gene. The c.-45 C>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.-45 C>T variant is not observed in large population cohorts; however, limited data are available (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position in the 5' untranslated region that is conserved in mammals. To our knowledge, regulatory variants in GARS have not been published in association with neuropathy (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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