chr7-30621454-G-A

Variant names:

• chr7-30621454-G-A
• rs1345590827
• NM_002047.4:c.1421G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_002047.4(GARS1):​c.1421G>A​(p.Arg474Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. R474P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.36

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-30621454-G-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.114702195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1421G>A	p.Arg474Gln	missense_variant	Exon 11 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1259G>A	p.Arg420Gln	missense_variant	Exon 11 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1421G>A	p.Arg474Gln	missense_variant	Exon 11 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1421G>A	p.Arg474Gln	missense_variant	Exon 11 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1319G>A	p.Arg440Gln	missense_variant	Exon 10 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1253G>A	p.Arg418Gln	missense_variant	Exon 12 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1220G>A	p.Arg407Gln	missense_variant	Exon 11 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1052G>A	p.Arg351Gln	missense_variant	Exon 11 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1052G>A	p.Arg351Gln	missense_variant	Exon 12 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1421G>A		non_coding_transcript_exon_variant	Exon 11 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1135G>A		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*521G>A		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*759G>A		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1421G>A		non_coding_transcript_exon_variant	Exon 11 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1291G>A		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1421G>A		non_coding_transcript_exon_variant	Exon 11 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1363G>A		non_coding_transcript_exon_variant	Exon 13 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*366G>A		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*872G>A		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*710G>A		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*853G>A		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1421G>A		non_coding_transcript_exon_variant	Exon 11 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*1135G>A		3_prime_UTR_variant	Exon 12 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*521G>A		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*759G>A		3_prime_UTR_variant	Exon 12 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*1291G>A		3_prime_UTR_variant	Exon 12 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1363G>A		3_prime_UTR_variant	Exon 13 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*366G>A		3_prime_UTR_variant	Exon 11 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*872G>A		3_prime_UTR_variant	Exon 11 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*710G>A		3_prime_UTR_variant	Exon 12 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*853G>A		3_prime_UTR_variant	Exon 11 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249576 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135406

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jul 19, 2017

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. This sequence change replaces arginine with glutamine at codon 474 of the GARS protein (p.Arg474Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GARS-related disease. 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 glutamine 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.55	T
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.20
Sift	Benign	0.32	T
Sift4G	Benign	0.21	T
Polyphen		0.0050	B
Vest4		0.18
MutPred		0.35		Gain of ubiquitination at K477 (P = 0.0357);
MVP		0.37
MPC		0.40
ClinPred		0.25	T
GERP RS		2.4
Varity_R		0.070
gMVP		0.40

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: rs1345590827; hg19: chr7-30661070;