rs2527878

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002047.4(GARS1):c.1032-23A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 1,613,316 control chromosomes in the GnomAD database, including 8,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.10 ( 867 hom., cov: 33)

Exomes 𝑓: 0.097 ( 7956 hom. )

Consequence

GARS1
NM_002047.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.148

Publications

11 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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 2D
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
neuronopathy, distal hereditary motor, type 5A
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Laboratory for Molecular Medicine
spinal muscular atrophy, infantile, James type
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

GARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 7-30615873-A-T is Benign according to our data. Variant chr7-30615873-A-T is described in ClinVar as Benign. ClinVar VariationId is 258531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1032-23A>T		intron_variant	Intron 8 of 16	ENST00000389266.8	NP_002038.2	P41250-1
GARS1	NM_001316772.1 link	c.870-23A>T		intron_variant	Intron 8 of 16		NP_001303701.1	P41250-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GARS1	ENST00000389266.8 link	c.1032-23A>T	intron_variant	Intron 8 of 16	1	NM_002047.4	ENSP00000373918.3	P41250-1
GARS1	ENST00000675651.1 link	c.1032-23A>T	intron_variant	Intron 8 of 16			ENSP00000502513.1	A0A6Q8PGZ8
GARS1	ENST00000675810.1 link	c.930-23A>T	intron_variant	Intron 7 of 15			ENSP00000502743.1	A0A6Q8PHH9
GARS1	ENST00000675693.1 link	c.864-23A>T	intron_variant	Intron 9 of 17			ENSP00000502174.1	A0A6Q8PGA8
GARS1	ENST00000675051.1 link	c.831-23A>T	intron_variant	Intron 8 of 16			ENSP00000502296.1	A0A6Q8PGI6
GARS1	ENST00000674815.1 link	c.663-23A>T	intron_variant	Intron 8 of 16			ENSP00000502799.1	A0A6Q8PGW4
GARS1	ENST00000674851.1 link	c.663-23A>T	intron_variant	Intron 9 of 17			ENSP00000502451.1	A0A6Q8PGW4
GARS1	ENST00000444666.6 link	n.1032-23A>T	intron_variant	Intron 8 of 17	3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 link	n.*746-23A>T	intron_variant	Intron 9 of 17			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 link	n.*132-23A>T	intron_variant	Intron 9 of 16			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 link	n.*370-23A>T	intron_variant	Intron 9 of 17			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000674807.1 link	n.1032-23A>T	intron_variant	Intron 8 of 15			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 link	n.*902-23A>T	intron_variant	Intron 9 of 17			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000675859.1 link	n.1032-23A>T	intron_variant	Intron 8 of 14			ENSP00000502033.1	A0A6Q8PFZ6
GARS1	ENST00000676088.1 link	n.*974-23A>T	intron_variant	Intron 10 of 18			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 link	n.1032-25A>T	intron_variant	Intron 8 of 16			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 link	n.*483-23A>T	intron_variant	Intron 8 of 16			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 link	n.*321-23A>T	intron_variant	Intron 9 of 17			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 link	n.*464-23A>T	intron_variant	Intron 8 of 16			ENSP00000501980.1	A0A6Q8PFU7
GARS1	ENST00000676403.1 link	n.1032-23A>T	intron_variant	Intron 8 of 15			ENSP00000502681.1	A0A6Q8PHI7

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15373

AN:

152088

Hom.:

865

Cov.:

show subpopulations

Gnomad AFR

AF:

0.118

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0931

Gnomad ASJ

AF:

0.0939

Gnomad EAS

AF:

0.180

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.0614

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0868

Gnomad OTH

AF:

0.125

GnomAD2 exomes

AF:

0.107

AC:

26655

AN:

249006

AF XY:

0.111

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.0753

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.165

Gnomad FIN exome

AF:

0.0624

Gnomad NFE exome

AF:

0.0918

Gnomad OTH exome

AF:

0.106

GnomAD4 exome

AF:

0.0969

AC:

141647

AN:

1461110

Hom.:

7956

Cov.:

AF XY:

0.0996

AC XY:

72413

AN XY:

726854

show subpopulations

African (AFR)

AF:

0.118

AC:

3942

AN:

33456

American (AMR)

AF:

0.0767

AC:

3427

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

2624

AN:

26128

East Asian (EAS)

AF:

0.192

AC:

7621

AN:

39694

South Asian (SAS)

AF:

0.187

AC:

16138

AN:

86176

European-Finnish (FIN)

AF:

0.0623

AC:

3325

AN:

53390

Middle Eastern (MID)

AF:

0.147

AC:

849

AN:

5758

European-Non Finnish (NFE)

AF:

0.0874

AC:

97189

AN:

1111466

Other (OTH)

AF:

0.108

AC:

6532

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

5919

11837

17756

23674

29593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3718

7436

11154

14872

18590

<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:

0.101

AC:

15382

AN:

152206

Hom.:

867

Cov.:

AF XY:

0.102

AC XY:

7585

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.118

AC:

4883

AN:

41520

American (AMR)

AF:

0.0929

AC:

1421

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0939

AC:

326

AN:

3472

East Asian (EAS)

AF:

0.181

AC:

934

AN:

5174

South Asian (SAS)

AF:

0.197

AC:

948

AN:

4822

European-Finnish (FIN)

AF:

0.0614

AC:

651

AN:

10606

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0868

AC:

5903

AN:

68008

Other (OTH)

AF:

0.129

AC:

271

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

713

1427

2140

2854

3567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<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:

0.0949

Hom.:

141

Bravo

AF:

0.105

Asia WGS

AF:

0.214

AC:

743

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.33

(source)

DANN

Benign

0.45

PhyloP100

-0.15

La Branchor

0.71

BranchPoint Hunter

2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over