rs1060502836

Positions:

• chr7-30616050-G-A

Variant summary

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

The NM_002047.4(GARS1):​c.1186G>A​(p.Val396Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.89

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 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/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1186G>A	p.Val396Ile	missense_variant	9/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1024G>A	p.Val342Ile	missense_variant	9/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1186G>A	p.Val396Ile	missense_variant	9/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1186G>A	p.Val396Ile	missense_variant	9/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1084G>A	p.Val362Ile	missense_variant	8/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1018G>A	p.Val340Ile	missense_variant	10/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.985G>A	p.Val329Ile	missense_variant	9/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.817G>A	p.Val273Ile	missense_variant	9/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.817G>A	p.Val273Ile	missense_variant	10/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1186G>A		non_coding_transcript_exon_variant	9/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*900G>A		non_coding_transcript_exon_variant	10/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*286G>A		non_coding_transcript_exon_variant	10/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*524G>A		non_coding_transcript_exon_variant	10/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1186G>A		non_coding_transcript_exon_variant	9/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1056G>A		non_coding_transcript_exon_variant	10/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1186G>A		non_coding_transcript_exon_variant	9/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1128G>A		non_coding_transcript_exon_variant	11/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*131G>A		non_coding_transcript_exon_variant	9/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*637G>A		non_coding_transcript_exon_variant	9/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*475G>A		non_coding_transcript_exon_variant	10/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*618G>A		non_coding_transcript_exon_variant	9/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1186G>A		non_coding_transcript_exon_variant	9/16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*900G>A		3_prime_UTR_variant	10/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*286G>A		3_prime_UTR_variant	10/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*524G>A		3_prime_UTR_variant	10/18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*1056G>A		3_prime_UTR_variant	10/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1128G>A		3_prime_UTR_variant	11/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*131G>A		3_prime_UTR_variant	9/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*637G>A		3_prime_UTR_variant	9/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*475G>A		3_prime_UTR_variant	10/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*618G>A		3_prime_UTR_variant	9/17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Charcot-Marie-Tooth disease type 2D;CN031873:Neuronopathy, distal hereditary motor, type 5A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2020

This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant has not been reported in the literature in individuals with GARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 410310). This sequence change replaces valine with isoleucine at codon 396 of the GARS protein (p.Val396Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.15	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.52
Sift	Benign	0.030	D
Sift4G	Uncertain	0.034	D
Polyphen		0.90	P
Vest4		0.57
MutPred		0.75		Gain of sheet (P = 0.0827);
MVP		0.69
MPC		0.32
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.49
gMVP		0.59

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: rs1060502836; hg19: chr7-30655666;