7-30594966-TCTG-TCTGCTGCTG

Position:

• chr7-30594966-TCTG-TCTGCTGCTG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BS1_Supporting BS2

The NM_002047.4(GARS1):​c.56_61dupTGCTGC​(p.Leu19_Leu20dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000653 in 1,593,314 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: GARS1 NM_002047.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.30

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]

GARS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_002047.4
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000687 (99/1441316) while in subpopulation NFE AF= 0.0000839 (93/1108468). AF 95% confidence interval is 0.0000698. There are 0 homozygotes in gnomad4_exome. There are 57 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.56_61dupTGCTGC	p.Leu19_Leu20dup	disruptive_inframe_insertion	1/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.-107_-102dupTGCTGC		5_prime_UTR_variant	1/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.56_61dupTGCTGC	p.Leu19_Leu20dup	disruptive_inframe_insertion	1/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.56_61dupTGCTGC	p.Leu19_Leu20dup	disruptive_inframe_insertion	1/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.56_61dupTGCTGC	p.Leu19_Leu20dup	disruptive_inframe_insertion	1/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.18+38_18+43dupTGCTGC		intron_variant				ENSP00000502174.1
GARS1	ENST00000675051.1	c.22-3819_22-3814dupTGCTGC		intron_variant				ENSP00000502296.1
GARS1	ENST00000674815.1	c.-148+25_-148+30dupTGCTGC		intron_variant				ENSP00000502799.1
GARS1	ENST00000674851.1	c.-184+25_-184+30dupTGCTGC		intron_variant				ENSP00000502451.1
GARS1	ENST00000444666.6	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.56_61dupTGCTGC		non_coding_transcript_exon_variant	1/16			ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151998 Hom.: 0 Cov.: 33

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000299 AC: 6 AN: 200818 Hom.: 0 AF XY: 0.0000358 AC XY: 4 AN XY: 111774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000316

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: 0.0000556

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000687 AC: 99 AN: 1441316 Hom.: 0 Cov.: 30 AF XY: 0.0000795 AC XY: 57 AN XY: 717226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000839

Gnomad4 OTH exome AF: 0.0000668

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151998 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74256

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: 0.0000736

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000642

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2021	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-frame insertion of 2 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 10, 2023

This variant, c.56_61dup, results in the insertion of 2 amino acid(s) of the GARS protein (p.Leu19_Leu20dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760759910, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with GARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 543196). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs150213018; hg19: chr7-30634582;