NM_002047.4:c.344A>G

Variant names:

• chr7-30599966-A-G
• rs1554336991
• NM_002047.4:c.344A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002047.4(GARS1):​c.344A>G​(p.Lys115Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24022084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.344A>G	p.Lys115Arg	missense_variant	Exon 3 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.182A>G	p.Lys61Arg	missense_variant	Exon 3 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.344A>G	p.Lys115Arg	missense_variant	Exon 3 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.344A>G	p.Lys115Arg	missense_variant	Exon 3 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.242A>G	p.Lys81Arg	missense_variant	Exon 2 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.176A>G	p.Lys59Arg	missense_variant	Exon 4 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.143A>G	p.Lys48Arg	missense_variant	Exon 3 of 17			ENSP00000502296.1
GARS1	ENST00000674815	c.-26A>G		5_prime_UTR_variant	Exon 3 of 17			ENSP00000502799.1
GARS1	ENST00000674851	c.-26A>G		5_prime_UTR_variant	Exon 4 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.344A>G		non_coding_transcript_exon_variant	Exon 3 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*58A>G		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.344A>G		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.344A>G		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.344A>G		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*214A>G		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.344A>G		non_coding_transcript_exon_variant	Exon 3 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*214A>G		non_coding_transcript_exon_variant	Exon 4 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.344A>G		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.344A>G		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.344A>G		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.344A>G		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.344A>G		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*58A>G		3_prime_UTR_variant	Exon 4 of 18			ENSP00000502408.1
GARS1	ENST00000675529.1	n.*214A>G		3_prime_UTR_variant	Exon 4 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*214A>G		3_prime_UTR_variant	Exon 4 of 19			ENSP00000501884.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461572 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727100

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Mar 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 115 of the GARS protein (p.Lys115Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 476756). 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 with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.15
Sift	Benign	0.20	T
Sift4G	Benign	0.17	T
Polyphen		0.049	B
Vest4		0.47
MutPred		0.41		Loss of ubiquitination at K115 (P = 0.0051);
MVP		0.40
MPC		0.42
ClinPred		0.93	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs1554336991; hg19: chr7-30639582;