7-30594966-TCTG-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3BP6_Moderate

The NM_002047.4(GARS1):c.59_61delTGC(p.Leu20del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,432,794 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GARS1
NM_002047.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:4

Conservation

PhyloP100: 2.30

Publications

2 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: Likely_benign. The variant received -3 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_002047.4

BP6

Variant 7-30594966-TCTG-T is Benign according to our data. Variant chr7-30594966-TCTG-T is described in ClinVar as Benign. ClinVar VariationId is 416092.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.59_61delTGC	p.Leu20del	disruptive_inframe_deletion	Exon 1 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.-104_-102delTGC		5_prime_UTR_variant	Exon 1 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GARS1	ENST00000389266.8 link	c.59_61delTGC	p.Leu20del	disruptive_inframe_deletion	Exon 1 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.59_61delTGC	p.Leu20del	disruptive_inframe_deletion	Exon 1 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.59_61delTGC	p.Leu20del	disruptive_inframe_deletion	Exon 1 of 16			ENSP00000502743.1
GARS1	ENST00000444666.6 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.59_61delTGC		non_coding_transcript_exon_variant	Exon 1 of 16			ENSP00000502681.1
GARS1	ENST00000675693.1 link	c.18+41_18+43delTGC		intron_variant	Intron 1 of 17			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.22-3816_22-3814delTGC		intron_variant	Intron 1 of 16			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.-148+28_-148+30delTGC		intron_variant	Intron 1 of 16			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.-184+28_-184+30delTGC		intron_variant	Intron 1 of 17			ENSP00000502451.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151984

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00202

AC:

405

AN:

200818

AF XY:

0.00211

show subpopulations

Gnomad AFR exome

AF:

0.00456

Gnomad AMR exome

AF:

0.00111

Gnomad ASJ exome

AF:

0.00143

Gnomad EAS exome

AF:

0.00145

Gnomad FIN exome

AF:

0.00233

Gnomad NFE exome

AF:

0.00239

Gnomad OTH exome

AF:

0.000774

GnomAD4 exome

AF:

0.000190

AC:

272

AN:

1432794

Hom.:

AF XY:

0.000226

AC XY:

161

AN XY:

713094

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000121

AC:

AN:

33130

American (AMR)

AF:

0.000730

AC:

AN:

43846

Ashkenazi Jewish (ASJ)

AF:

0.000426

AC:

AN:

25808

East Asian (EAS)

AF:

0.000127

AC:

AN:

39252

South Asian (SAS)

AF:

0.000484

AC:

AN:

84788

European-Finnish (FIN)

AF:

0.000688

AC:

AN:

39248

Middle Eastern (MID)

AF:

0.000393

AC:

AN:

5092

European-Non Finnish (NFE)

AF:

0.000125

AC:

138

AN:

1102066

Other (OTH)

AF:

0.000201

AC:

AN:

59564

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.253

Heterozygous variant carriers

121

161

201

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

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

151984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74248

African (AFR)

AF:

0.00

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2086

Alfa

AF:

0.00274

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GARS1-related disorder

Benign:1

Jul 16, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Charcot-Marie-Tooth disease type 2

Benign:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over