rs137852644

Variant names:

• chr7-30601179-T-C
• rs137852644
• NM_002047.4:c.548T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_002047.4(GARS1):​c.548T>C​(p.Leu183Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L183F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:2 O:1
• Conservation: PhyloP100: 7.93
• Publications: 37 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 7-30601179-T-C is Pathogenic according to our data. Variant chr7-30601179-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 9205.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002047.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	NM_002047.4	MANE Select	c.548T>C	p.Leu183Pro	missense	Exon 4 of 17	NP_002038.2
	GARS1	NM_001316772.1		c.386T>C	p.Leu129Pro	missense	Exon 4 of 17	NP_001303701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000389266.8	TSL:1 MANE Select	c.548T>C	p.Leu183Pro	missense	Exon 4 of 17	ENSP00000373918.3
	GARS1	ENST00000675651.1		c.548T>C	p.Leu183Pro	missense	Exon 4 of 17	ENSP00000502513.1
	GARS1	ENST00000675810.1		c.446T>C	p.Leu149Pro	missense	Exon 3 of 16	ENSP00000502743.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000654 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2D Uncertain:1 Other:1

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

GARS1-HMSN (exclusively dSMA-V) [Antonellis et al 2003, He et al 2015]

not provided Pathogenic:1

Dec 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neuronopathy, distal hereditary motor, type 5A Pathogenic:1

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Charcot-Marie-Tooth disease Uncertain:1

Aug 14, 2019

Genesis Genome Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.56	D
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.96		Gain of disorder (P = 0.0222)
MVP		0.76
MPC		1.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.97
gMVP		0.96
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852644; hg19: chr7-30640795;