7-30616026-C-T

Variant names:

• chr7-30616026-C-T
• rs759277467
• NM_002047.4:c.1162C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_002047.4(GARS1):​c.1162C>T​(p.Arg388Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R388G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.97
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 2D

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, type 5A

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Laboratory for Molecular Medicine
• spinal muscular atrophy, infantile, James type

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000198 (29/1461892) while in subpopulation SAS AF = 0.0000348 (3/86258). AF 95% confidence interval is 0.0000146. There are 0 homozygotes in GnomAdExome4. There are 15 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 29 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002047.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	NM_002047.4	MANE Select	c.1162C>T	p.Arg388Trp	missense	Exon 9 of 17	NP_002038.2
	GARS1	NM_001316772.1		c.1000C>T	p.Arg334Trp	missense	Exon 9 of 17	NP_001303701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000389266.8	TSL:1 MANE Select	c.1162C>T	p.Arg388Trp	missense	Exon 9 of 17	ENSP00000373918.3
	GARS1	ENST00000675651.1		c.1162C>T	p.Arg388Trp	missense	Exon 9 of 17	ENSP00000502513.1
	GARS1	ENST00000675810.1		c.1060C>T	p.Arg354Trp	missense	Exon 8 of 16	ENSP00000502743.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249522 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000827 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1162C>T (p.R388W) alteration is located in exon 9 (coding exon 9) of the GARS gene. This alteration results from a C to T substitution at nucleotide position 1162, causing the arginine (R) at amino acid position 388 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Spinal muscular atrophy, infantile, James type Uncertain:1

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charcot-Marie-Tooth disease type 2 Uncertain:1

Sep 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces arginine with tryptophan at codon 388 of the GARS protein (p.Arg388Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs759277467, ExAC 0.009%). This missense change has been observed in individual(s) with clinical suspicion of Charcot-Marie-Tooth disease (PMID: 25614874). ClinVar contains an entry for this variant (Variation ID: 585898). 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: "Possibly Damaging"; Align-GVGD: "Class C0").

not provided Uncertain:1

May 16, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0017	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.037	D
PhyloP100		4.0
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.019	D
Polyphen		0.99	D
Vest4		0.39
MutPred		0.45		Loss of disorder (P = 0.0019)
MVP		0.56
MPC		0.90
ClinPred		0.95	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.45
gMVP		0.52
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs759277467; hg19: chr7-30655642; COSMIC: COSV66827925;