NM_002047.4:c.246_249delAGAA

Variant names:

• chr7-30598816-CAAAG-C
• rs1135401747
• NM_002047.4:c.246_249delAGAA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_002047.4(GARS1):​c.246_249delAGAA​(p.Glu83IlefsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GARS1 NM_002047.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.67

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-30598816-CAAAG-C is Pathogenic according to our data. Variant chr7-30598816-CAAAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 431180.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.246_249delAGAA	p.Glu83IlefsTer6	frameshift_variant	Exon 2 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.84_87delAGAA	p.Glu29IlefsTer6	frameshift_variant	Exon 2 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.246_249delAGAA	p.Glu83IlefsTer6	frameshift_variant	Exon 2 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.246_249delAGAA	p.Glu83IlefsTer6	frameshift_variant	Exon 2 of 17			ENSP00000502513.1
GARS1	ENST00000675693.1	c.78_81delAGAA	p.Glu27IlefsTer6	frameshift_variant	Exon 3 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.45_48delAGAA	p.Glu16IlefsTer6	frameshift_variant	Exon 2 of 17			ENSP00000502296.1
GARS1	ENST00000674815	c.-124_-121delAGAA		5_prime_UTR_variant	Exon 2 of 17			ENSP00000502799.1
GARS1	ENST00000674851	c.-124_-121delAGAA		5_prime_UTR_variant	Exon 3 of 18			ENSP00000502451.1
GARS1	ENST00000675810.1	c.223-1128_223-1125delAGAA		intron_variant	Intron 1 of 15			ENSP00000502743.1
GARS1	ENST00000444666.6	n.246_249delAGAA		non_coding_transcript_exon_variant	Exon 2 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.246_249delAGAA		non_coding_transcript_exon_variant	Exon 2 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.246_249delAGAA		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.246_249delAGAA		non_coding_transcript_exon_variant	Exon 2 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.246_249delAGAA		non_coding_transcript_exon_variant	Exon 2 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*116_*119delAGAA		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.246_249delAGAA		non_coding_transcript_exon_variant	Exon 2 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*116_*119delAGAA		non_coding_transcript_exon_variant	Exon 3 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.246_249delAGAA		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.246_249delAGAA		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.246_249delAGAA		non_coding_transcript_exon_variant	Exon 2 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.246_249delAGAA		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.246_249delAGAA		non_coding_transcript_exon_variant	Exon 2 of 16			ENSP00000502681.1
GARS1	ENST00000675529.1	n.*116_*119delAGAA		3_prime_UTR_variant	Exon 3 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*116_*119delAGAA		3_prime_UTR_variant	Exon 3 of 19			ENSP00000501884.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461740 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

GARS-associated growth retardation and developmental delay Pathogenic:1

-

Antonellis Laboratory at Michigan, University of Michigan

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing;research

This variant is associated with a recessive, multi-system disorder described in PMID: 28675565. -

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: rs1135401747; hg19: chr7-30638432;