rs201728920

Positions:

• chr7-30598835-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_002047.4(GARS1):​c.262C>G​(p.Gln88Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.31

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07979828).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000329 (5/152104) while in subpopulation AMR AF= 0.000196 (3/15276). AF 95% confidence interval is 0.0000529. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.262C>G	p.Gln88Glu	missense_variant	2/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.100C>G	p.Gln34Glu	missense_variant	2/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.262C>G	p.Gln88Glu	missense_variant	2/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.262C>G	p.Gln88Glu	missense_variant	2/17			ENSP00000502513.1
GARS1	ENST00000675693.1	c.94C>G	p.Gln32Glu	missense_variant	3/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.61C>G	p.Gln21Glu	missense_variant	2/17			ENSP00000502296.1
GARS1	ENST00000674815	c.-108C>G		5_prime_UTR_variant	2/17			ENSP00000502799.1
GARS1	ENST00000674851	c.-108C>G		5_prime_UTR_variant	3/18			ENSP00000502451.1
GARS1	ENST00000675810.1	c.223-1112C>G		intron_variant				ENSP00000502743.1
GARS1	ENST00000444666.6	n.262C>G		non_coding_transcript_exon_variant	2/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.262C>G		non_coding_transcript_exon_variant	2/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.262C>G		non_coding_transcript_exon_variant	2/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.262C>G		non_coding_transcript_exon_variant	2/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.262C>G		non_coding_transcript_exon_variant	2/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*132C>G		non_coding_transcript_exon_variant	3/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.262C>G		non_coding_transcript_exon_variant	2/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*132C>G		non_coding_transcript_exon_variant	3/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.262C>G		non_coding_transcript_exon_variant	2/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.262C>G		non_coding_transcript_exon_variant	2/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.262C>G		non_coding_transcript_exon_variant	2/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.262C>G		non_coding_transcript_exon_variant	2/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.262C>G		non_coding_transcript_exon_variant	2/16			ENSP00000502681.1
GARS1	ENST00000675529.1	n.*132C>G		3_prime_UTR_variant	3/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*132C>G		3_prime_UTR_variant	3/19			ENSP00000501884.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000481 AC: 12 AN: 249512 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135390

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

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: 0.0000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000216

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000579 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2022

The p.Q88E variant (also known as c.262C>G), located in coding exon 2 of the GARS gene, results from a C to G substitution at nucleotide position 262. The glutamine at codon 88 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration was detected in an individual with pes cavus in a neuromuscular disease testing cohort; however, clinical details were limited (Gonzalez-Quereda L et al. Genes (Basel), 2020 05;11:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of Charcot-Marie Tooth type 2D (CMT2D) and distal hereditary motor neuronopathy type VA; however, its contribution to the development of GARS-related mitochondrial respiratory chain dysfunction is uncertain. -

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

Mar 18, 2022

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 410311). This variant has not been reported in the literature in individuals affected with GARS-related conditions. This variant is present in population databases (rs201728920, gnomAD 0.009%). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 88 of the GARS protein (p.Gln88Glu). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.24
Eigen_PC	Benign	0.0023
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.064
Sift	Benign	0.73	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.40		Loss of MoRF binding (P = 0.0661);
MVP		0.16
MPC		0.38
ClinPred		0.045	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
gMVP		0.35

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: rs201728920; hg19: chr7-30638451;