chr7-30600040-A-C

Variant names:

• chr7-30600040-A-C
• rs888805042
• NM_002047.4:c.418A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002047.4(GARS1):​c.418A>C​(p.Ile140Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,510 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• 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: 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.418A>C	p.Ile140Leu	missense_variant	Exon 3 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.256A>C	p.Ile86Leu	missense_variant	Exon 3 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.418A>C	p.Ile140Leu	missense_variant	Exon 3 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.418A>C	p.Ile140Leu	missense_variant	Exon 3 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.316A>C	p.Ile106Leu	missense_variant	Exon 2 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.250A>C	p.Ile84Leu	missense_variant	Exon 4 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.217A>C	p.Ile73Leu	missense_variant	Exon 3 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.49A>C	p.Ile17Leu	missense_variant	Exon 3 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.49A>C	p.Ile17Leu	missense_variant	Exon 4 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*132A>C		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*288A>C		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*288A>C		non_coding_transcript_exon_variant	Exon 4 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.418A>C		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*132A>C		3_prime_UTR_variant	Exon 4 of 18			ENSP00000502408.1
GARS1	ENST00000675529.1	n.*288A>C		3_prime_UTR_variant	Exon 4 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*288A>C		3_prime_UTR_variant	Exon 4 of 19			ENSP00000501884.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457510 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725420

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

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

Sep 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with leucine at codon 140 of the GARS protein (p.Ile140Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with GARS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.29	T
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.027	D
Sift4G	Benign	0.063	T
Polyphen		0.044	B
Vest4		0.77
MutPred		0.69		Loss of catalytic residue at I140 (P = 0.0322);
MVP		0.89
MPC		0.36
ClinPred		0.81	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.75

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: rs888805042; hg19: chr7-30639656;