chr7-30622336-A-G

Variant names:

• chr7-30622336-A-G
• rs1325522512
• NM_002047.4:c.1487A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002047.4(GARS1):​c.1487A>G​(p.Gln496Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1487A>G	p.Gln496Arg	missense_variant	Exon 12 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1325A>G	p.Gln442Arg	missense_variant	Exon 12 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1487A>G	p.Gln496Arg	missense_variant	Exon 12 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1487A>G	p.Gln496Arg	missense_variant	Exon 12 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1385A>G	p.Gln462Arg	missense_variant	Exon 11 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1319A>G	p.Gln440Arg	missense_variant	Exon 13 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1286A>G	p.Gln429Arg	missense_variant	Exon 12 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1118A>G	p.Gln373Arg	missense_variant	Exon 12 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1118A>G	p.Gln373Arg	missense_variant	Exon 13 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1487A>G		non_coding_transcript_exon_variant	Exon 12 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1201A>G		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*587A>G		non_coding_transcript_exon_variant	Exon 13 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*825A>G		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1487A>G		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1357A>G		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1487A>G		non_coding_transcript_exon_variant	Exon 12 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1429A>G		non_coding_transcript_exon_variant	Exon 14 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*432A>G		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*938A>G		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*776A>G		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*919A>G		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1487A>G		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*1201A>G		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*587A>G		3_prime_UTR_variant	Exon 13 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*825A>G		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*1357A>G		3_prime_UTR_variant	Exon 13 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1429A>G		3_prime_UTR_variant	Exon 14 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*432A>G		3_prime_UTR_variant	Exon 12 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*938A>G		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*776A>G		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*919A>G		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74378

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Apr 29, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 476751). 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 glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 496 of the GARS protein (p.Gln496Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.24	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.61
Sift	Benign	0.23	T
Sift4G	Benign	0.18	T
Polyphen		0.0050	B
Vest4		0.88
MutPred		0.55		Gain of MoRF binding (P = 0.0249);
MVP		0.99
MPC		0.44
ClinPred		0.76	D
GERP RS		5.4
Varity_R		0.22
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1325522512; hg19: chr7-30661952;