chr7-30622417-A-G

Variant names:

• chr7-30622417-A-G
• rs779225125
• NM_002047.4:c.1568A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002047.4(GARS1):​c.1568A>G​(p.Asp523Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,844 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: 0.0000014 (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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35965383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1568A>G	p.Asp523Gly	missense_variant	Exon 12 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1406A>G	p.Asp469Gly	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.1568A>G	p.Asp523Gly	missense_variant	Exon 12 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1568A>G	p.Asp523Gly	missense_variant	Exon 12 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1466A>G	p.Asp489Gly	missense_variant	Exon 11 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1400A>G	p.Asp467Gly	missense_variant	Exon 13 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1367A>G	p.Asp456Gly	missense_variant	Exon 12 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1199A>G	p.Asp400Gly	missense_variant	Exon 12 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1199A>G	p.Asp400Gly	missense_variant	Exon 13 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1568A>G		non_coding_transcript_exon_variant	Exon 12 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1282A>G		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*668A>G		non_coding_transcript_exon_variant	Exon 13 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*906A>G		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1568A>G		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1438A>G		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1568A>G		non_coding_transcript_exon_variant	Exon 12 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1510A>G		non_coding_transcript_exon_variant	Exon 14 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*513A>G		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1019A>G		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*857A>G		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1000A>G		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1568A>G		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*1282A>G		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*668A>G		3_prime_UTR_variant	Exon 13 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*906A>G		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*1438A>G		3_prime_UTR_variant	Exon 13 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1510A>G		3_prime_UTR_variant	Exon 14 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*513A>G		3_prime_UTR_variant	Exon 12 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1019A>G		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*857A>G		3_prime_UTR_variant	Exon 13 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1000A>G		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249560 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135392

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: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 23, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26138142, 25168514) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	0.0086	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.094	T
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.49
Sift	Benign	0.054	T
Sift4G	Uncertain	0.040	D
Polyphen		0.0010	B
Vest4		0.38
MutPred		0.60		Loss of sheet (P = 0.1158);
MVP		0.77
MPC		0.51
ClinPred		0.83	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: 45

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs779225125; hg19: chr7-30662033;