NM_002047.4:c.450T>A

Variant names:

• chr7-30601081-T-A
• rs751505742
• NM_002047.4:c.450T>A

Variant summary

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

The NM_002047.4(GARS1):​c.450T>A​(p.Phe150Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.200
• Publications: 2 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: 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	c.450T>A	p.Phe150Leu	missense_variant	Exon 4 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.288T>A	p.Phe96Leu	missense_variant	Exon 4 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.450T>A	p.Phe150Leu	missense_variant	Exon 4 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.450T>A	p.Phe150Leu	missense_variant	Exon 4 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.348T>A	p.Phe116Leu	missense_variant	Exon 3 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.282T>A	p.Phe94Leu	missense_variant	Exon 5 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.249T>A	p.Phe83Leu	missense_variant	Exon 4 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.81T>A	p.Phe27Leu	missense_variant	Exon 4 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.81T>A	p.Phe27Leu	missense_variant	Exon 5 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.450T>A		non_coding_transcript_exon_variant	Exon 4 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*164T>A		non_coding_transcript_exon_variant	Exon 5 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.450T>A		non_coding_transcript_exon_variant	Exon 4 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.450T>A		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.450T>A		non_coding_transcript_exon_variant	Exon 4 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*320T>A		non_coding_transcript_exon_variant	Exon 5 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.450T>A		non_coding_transcript_exon_variant	Exon 4 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*320T>A		non_coding_transcript_exon_variant	Exon 5 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.450T>A		non_coding_transcript_exon_variant	Exon 4 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.450T>A		non_coding_transcript_exon_variant	Exon 4 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.450T>A		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000502373.1
GARS1	ENST00000676403.1	n.450T>A		non_coding_transcript_exon_variant	Exon 4 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*164T>A		3_prime_UTR_variant	Exon 5 of 18			ENSP00000502408.1
GARS1	ENST00000675529.1	n.*320T>A		3_prime_UTR_variant	Exon 5 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*320T>A		3_prime_UTR_variant	Exon 5 of 19			ENSP00000501884.1
GARS1	ENST00000676259.1	n.428-48T>A		intron_variant	Intron 3 of 16			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Jan 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine with leucine at codon 150 of the GARS protein (p.Phe150Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with GARS-related disease. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.89	T
PhyloP100		0.20
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.025	D
Sift4G	Benign	0.14	T
Polyphen		0.0070	B
Vest4		0.48
MutPred		0.74		Loss of catalytic residue at F150 (P = 0.0622);
MVP		0.50
MPC		0.41
ClinPred		0.91	D
GERP RS		0.043
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.81
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs751505742; hg19: chr7-30640697;