7-30622417-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002047.4(GARS1):c.1568A>T(p.Asp523Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D523G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.29

Publications

1 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1568A>T	p.Asp523Val	missense_variant	Exon 12 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.1406A>T	p.Asp469Val	missense_variant	Exon 12 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GARS1	ENST00000389266.8 link	c.1568A>T	p.Asp523Val	missense_variant	Exon 12 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.1568A>T	p.Asp523Val	missense_variant	Exon 12 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.1466A>T	p.Asp489Val	missense_variant	Exon 11 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.1400A>T	p.Asp467Val	missense_variant	Exon 13 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.1367A>T	p.Asp456Val	missense_variant	Exon 12 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.1199A>T	p.Asp400Val	missense_variant	Exon 12 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.1199A>T	p.Asp400Val	missense_variant	Exon 13 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.1568A>T		non_coding_transcript_exon_variant	Exon 12 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*1282A>T		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*668A>T		non_coding_transcript_exon_variant	Exon 13 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*906A>T		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.1568A>T		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*1438A>T		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.1568A>T		non_coding_transcript_exon_variant	Exon 12 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*1510A>T		non_coding_transcript_exon_variant	Exon 14 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*513A>T		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*1019A>T		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*857A>T		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*1000A>T		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.1568A>T		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1 link	n.*1282A>T		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.*668A>T		3_prime_UTR_variant	Exon 13 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*906A>T		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1 link	n.*1438A>T		3_prime_UTR_variant	Exon 13 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*1510A>T		3_prime_UTR_variant	Exon 14 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.*513A>T		3_prime_UTR_variant	Exon 12 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*1019A>T		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*857A>T		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*1000A>T		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249560

AF XY:

0.00

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000137

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727222

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111988

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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

Cov.:

Alfa

AF:

0.000111

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2

Uncertain:1

Nov 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 188352). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GARS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with GARS-related conditions. This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 523 of the GARS protein (p.Asp523Val). This variant is present in population databases (rs779225125, gnomAD 0.0009%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.48

MetaSVM

Uncertain

0.26

PhyloP100

9.3

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.66

Sift

Uncertain

0.017

Sift4G

Uncertain

0.026

Polyphen

0.28

Vest4

0.46

MutPred

0.59

Gain of helix (P = 0.0225);

MVP

0.71

MPC

0.65

ClinPred

0.96

GERP RS

5.7

Varity_R

0.59

gMVP

0.65

Mutation Taster

=59/41

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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