Genetic Variant ENST00000675810.1:c.-45C>T (chr7-30594877-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

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

The ENST00000675810.1(GARS1):c.-45C>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
ENST00000675810.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.351

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 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 passed 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000675810.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GARS1	NM_001316772.1		c.-207C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001303701.1	P41250-2
GARS1	NM_001316772.1		c.-207C>T	5_prime_UTR	Exon 1 of 17	NP_001303701.1	P41250-2
GARS1	NM_002047.4	MANE Select	c.-45C>T	upstream_gene	N/A	NP_002038.2	P41250-1

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
GARS1	ENST00000675810.1	c.-45C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000502743.1	A0A6Q8PHH9
GARS1	ENST00000674815.1	c.-223C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000502799.1	A0A6Q8PGW4
GARS1	ENST00000675810.1	c.-45C>T	5_prime_UTR	Exon 1 of 16	ENSP00000502743.1	A0A6Q8PHH9

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

African (AFR)

AF:

0.00

AC:

AN:

29916

American (AMR)

AF:

0.0000569

AC:

AN:

35144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24662

East Asian (EAS)

AF:

0.00

AC:

AN:

35066

South Asian (SAS)

AF:

0.00

AC:

AN:

77692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3966

European-Non Finnish (NFE)

AF:

0.0000698

AC:

AN:

1030782

Other (OTH)

AF:

0.0000179

AC:

AN:

55808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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

AF:

0.0000460

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41442

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.568

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

0.35

PromoterAI

-0.052

Neutral

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over