rs879254345

Variant names:

• chr7-30628647-GAGA-G
• rs879254345
• NM_002047.4:c.1790_1792delAAG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_002047.4(GARS1):​c.1790_1792delAAG​(p.Glu597del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GARS1 NM_002047.4 disruptive_inframe_deletion
• 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
• PM4: Nonframeshift variant in NON repetitive region in NM_002047.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1790_1792delAAG	p.Glu597del	disruptive_inframe_deletion	Exon 14 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1628_1630delAAG	p.Glu543del	disruptive_inframe_deletion	Exon 14 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1790_1792delAAG	p.Glu597del	disruptive_inframe_deletion	Exon 14 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1790_1792delAAG	p.Glu597del	disruptive_inframe_deletion	Exon 14 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1688_1690delAAG	p.Glu563del	disruptive_inframe_deletion	Exon 13 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1622_1624delAAG	p.Glu541del	disruptive_inframe_deletion	Exon 15 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1589_1591delAAG	p.Glu530del	disruptive_inframe_deletion	Exon 14 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1421_1423delAAG	p.Glu474del	disruptive_inframe_deletion	Exon 14 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1421_1423delAAG	p.Glu474del	disruptive_inframe_deletion	Exon 15 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*211_*213delAAG		non_coding_transcript_exon_variant	Exon 15 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1504_*1506delAAG		non_coding_transcript_exon_variant	Exon 15 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*890_*892delAAG		non_coding_transcript_exon_variant	Exon 15 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1128_*1130delAAG		non_coding_transcript_exon_variant	Exon 15 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*63_*65delAAG		non_coding_transcript_exon_variant	Exon 13 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1660_*1662delAAG		non_coding_transcript_exon_variant	Exon 15 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*63_*65delAAG		non_coding_transcript_exon_variant	Exon 13 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1732_*1734delAAG		non_coding_transcript_exon_variant	Exon 16 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*735_*737delAAG		non_coding_transcript_exon_variant	Exon 14 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1241_*1243delAAG		non_coding_transcript_exon_variant	Exon 14 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1079_*1081delAAG		non_coding_transcript_exon_variant	Exon 15 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1222_*1224delAAG		non_coding_transcript_exon_variant	Exon 14 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1790_1792delAAG		non_coding_transcript_exon_variant	Exon 14 of 16			ENSP00000502681.1
GARS1	ENST00000444666.6	n.*211_*213delAAG		3_prime_UTR_variant	Exon 15 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1504_*1506delAAG		3_prime_UTR_variant	Exon 15 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*890_*892delAAG		3_prime_UTR_variant	Exon 15 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1128_*1130delAAG		3_prime_UTR_variant	Exon 15 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*63_*65delAAG		3_prime_UTR_variant	Exon 13 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1660_*1662delAAG		3_prime_UTR_variant	Exon 15 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*63_*65delAAG		3_prime_UTR_variant	Exon 13 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1732_*1734delAAG		3_prime_UTR_variant	Exon 16 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*735_*737delAAG		3_prime_UTR_variant	Exon 14 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1241_*1243delAAG		3_prime_UTR_variant	Exon 14 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1079_*1081delAAG		3_prime_UTR_variant	Exon 15 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1222_*1224delAAG		3_prime_UTR_variant	Exon 14 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

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

Feb 08, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this is a novel in-frame deletion with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This sequence change deletes 3 nucleotides from exon 14 of the GARS mRNA (c.1790_1792delAAG). This leads to the deletion of 1 amino acid residue(s) in the GARS protein (p.Glu597del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a GARS-related disease. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs879254345; hg19: chr7-30668263;