NM_002047.4:c.11C>G

Variant names:

• chr7-30594932-C-G
• rs62636572
• NM_002047.4:c.11C>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.11C>G​(p.Pro4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 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. P4L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.13

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-DT (HGNC:48951): (GARS1 divergent transcript)

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=0.119731665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.11C>G	p.Pro4Arg	missense_variant	Exon 1 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.-152C>G		5_prime_UTR_variant	Exon 1 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.11C>G	p.Pro4Arg	missense_variant	Exon 1 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.11C>G	p.Pro4Arg	missense_variant	Exon 1 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.11C>G	p.Pro4Arg	missense_variant	Exon 1 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.11C>G	p.Pro4Arg	missense_variant	Exon 1 of 18			ENSP00000502174.1
GARS1	ENST00000674815	c.-168C>G		5_prime_UTR_variant	Exon 1 of 17			ENSP00000502799.1
GARS1	ENST00000674851	c.-204C>G		5_prime_UTR_variant	Exon 1 of 18			ENSP00000502451.1
GARS1	ENST00000675051.1	c.22-3864C>G		intron_variant	Intron 1 of 16			ENSP00000502296.1
GARS1	ENST00000444666.6	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.11C>G		non_coding_transcript_exon_variant	Exon 1 of 16			ENSP00000502681.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438836 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 715370

Gnomad4 AFR exome AF: 0.00

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Aug 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with GARS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4 of the GARS protein (p.Pro4Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.39
DANN	Benign	0.83
DEOGEN2	Benign	0.072	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.45	T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.93	T
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.88	N;.
REVEL	Benign	0.17
Sift	Benign	0.14	T;.
Sift4G	Benign	0.14	T;T
Polyphen		0.026	B;.
Vest4		0.14
MutPred		0.24		Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);
MVP		0.41
MPC		0.37
ClinPred		0.089	T
GERP RS		-1.4
Varity_R		0.032
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs62636572; hg19: chr7-30634548;