7-30632247-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_002047.4(GARS1):c.1904C>T(p.Ser635Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S635W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense, splice_region

Scores

Splicing: ADA: 0.9823

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 7.88

Publications

25 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 -8 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 7-30632247-C-T is Benign according to our data. Variant chr7-30632247-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 209157.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000986 (15/152112) while in subpopulation AMR AF = 0.0000655 (1/15260). AF 95% confidence interval is 0.0000197. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1904C>T	p.Ser635Leu	missense_variant, splice_region_variant	Exon 16 of 17	ENST00000389266.8	NP_002038.2	P41250-1
GARS1	NM_001316772.1 link	c.1742C>T	p.Ser581Leu	missense_variant, splice_region_variant	Exon 16 of 17		NP_001303701.1	P41250-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GARS1	ENST00000389266.8 link	c.1904C>T	p.Ser635Leu	missense_variant, splice_region_variant	Exon 16 of 17	1	NM_002047.4	ENSP00000373918.3	P41250-1
GARS1	ENST00000675651.1 link	c.1922C>T	p.Ala641Val	missense_variant, splice_region_variant	Exon 16 of 17			ENSP00000502513.1	A0A6Q8PGZ8
GARS1	ENST00000675810.1 link	c.1802C>T	p.Ser601Leu	missense_variant, splice_region_variant	Exon 15 of 16			ENSP00000502743.1	A0A6Q8PHH9
GARS1	ENST00000675693.1 link	c.1736C>T	p.Ser579Leu	missense_variant, splice_region_variant	Exon 17 of 18			ENSP00000502174.1	A0A6Q8PGA8
GARS1	ENST00000675051.1 link	c.1703C>T	p.Ser568Leu	missense_variant, splice_region_variant	Exon 16 of 17			ENSP00000502296.1	A0A6Q8PGI6
GARS1	ENST00000674815.1 link	c.1535C>T	p.Ser512Leu	missense_variant, splice_region_variant	Exon 16 of 17			ENSP00000502799.1	A0A6Q8PGW4
GARS1	ENST00000674851.1 link	c.1535C>T	p.Ser512Leu	missense_variant, splice_region_variant	Exon 17 of 18			ENSP00000502451.1	A0A6Q8PGW4
GARS1	ENST00000444666.6 link	n.*325C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 18	3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 link	n.*1618C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 link	n.*1709C>T		non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 link	n.*1242C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000674807.1 link	n.*177C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 15 of 16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 link	n.*1774C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000675859.1 link	n.*83C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 15			ENSP00000502033.1	A0A6Q8PFZ6
GARS1	ENST00000676088.1 link	n.*1846C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 18 of 19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 link	n.*849C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 link	n.*1355C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 link	n.*1193C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 link	n.*1336C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000501980.1	A0A6Q8PFU7
GARS1	ENST00000676403.1 link	n.1810C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 15 of 16			ENSP00000502681.1	A0A6Q8PHI7
GARS1	ENST00000444666.6 link	n.*325C>T		3_prime_UTR_variant	Exon 17 of 18	3		ENSP00000415447.2	H7C443
GARS1	ENST00000674616.1 link	n.*1618C>T		3_prime_UTR_variant	Exon 17 of 18			ENSP00000502408.1	A0A6Q8PGT3
GARS1	ENST00000674643.1 link	n.*1709C>T		3_prime_UTR_variant	Exon 16 of 17			ENSP00000501636.1	A0A6Q8PF45
GARS1	ENST00000674737.1 link	n.*1242C>T		3_prime_UTR_variant	Exon 17 of 18			ENSP00000502464.1	A0A6Q8PGZ9
GARS1	ENST00000674807.1 link	n.*177C>T		3_prime_UTR_variant	Exon 15 of 16			ENSP00000502814.1	A0A6Q8PFZ6
GARS1	ENST00000675529.1 link	n.*1774C>T		3_prime_UTR_variant	Exon 17 of 18			ENSP00000501655.1	A0A6Q8PFN0
GARS1	ENST00000675859.1 link	n.*83C>T		3_prime_UTR_variant	Exon 14 of 15			ENSP00000502033.1	A0A6Q8PFZ6
GARS1	ENST00000676088.1 link	n.*1846C>T		3_prime_UTR_variant	Exon 18 of 19			ENSP00000501884.1	A0A6Q8PFN0
GARS1	ENST00000676140.1 link	n.*849C>T		3_prime_UTR_variant	Exon 16 of 17			ENSP00000502571.1	A0A6Q8PH49
GARS1	ENST00000676164.1 link	n.*1355C>T		3_prime_UTR_variant	Exon 16 of 17			ENSP00000501986.1	A0A6Q8PFV5
GARS1	ENST00000676210.1 link	n.*1193C>T		3_prime_UTR_variant	Exon 17 of 18			ENSP00000502373.1	A0A6Q8PGN7
GARS1	ENST00000676259.1 link	n.*1336C>T		3_prime_UTR_variant	Exon 16 of 17			ENSP00000501980.1	A0A6Q8PFU7

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000205

AC:

AN:

249178

AF XY:

0.000192

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00408

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000125

AC:

182

AN:

1461642

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.000134

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00448

AC:

117

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000414

AC:

AN:

1111816

Other (OTH)

AF:

0.000182

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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:

0.0000986

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41414

American (AMR)

AF:

0.0000655

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68038

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000325

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000244

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2D

Uncertain:2

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Charcot-Marie-Tooth disease

Uncertain:1

Inherited Neuropathy Consortium

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:1

Jun 16, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth disease type 2

Benign:1

Oct 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.28

MetaSVM

Uncertain

0.19

PhyloP100

7.9

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0090

Polyphen

0.80

Vest4

0.74

MVP

0.94

MPC

0.89

ClinPred

0.76

GERP RS

5.3

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.84

gMVP

0.85

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.78

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

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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