rs1060502838

Positions:

• chr7-30621448-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_002047.4(GARS1):​c.1415A>G​(p.His472Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:3 O: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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 9) in uniprot entity GARS_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002047.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-30621448-A-G is Pathogenic according to our data. Variant chr7-30621448-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 410314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30621448-A-G is described in Lovd as [Pathogenic]. Variant chr7-30621448-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GARS1	NM_002047.4	c.1415A>G	p.His472Arg	missense_variant	11/17	ENST00000389266.8
GARS1	NM_001316772.1	c.1253A>G	p.His418Arg	missense_variant	11/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GARS1	ENST00000389266.8	c.1415A>G	p.His472Arg	missense_variant	11/17	1	NM_002047.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronopathy, distal hereditary motor, type 5A Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Cologne University	Apr 25, 2018	- -

Charcot-Marie-Tooth disease type 2D Uncertain:1 Other:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Apr 20, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	GARS1-HMSN (exclusively dSMA-V) [Sivakumar et al 2005, Griffin et al 2014, Cortese et al 2020, Lin et al 2020] -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2019

The p.H472R variant (also known as c.1415A>G), located in coding exon 11 of the GARS gene, results from an A to G substitution at nucleotide position 1415. The histidine at codon 472 is replaced by arginine, an amino acid with highly similar properties. This variant (also referred to as p.H418R) has been reported in multiple patients with distal hereditary motor neuropathy (also called distal spinal muscular atrophy) and has been shown to segregate with disease (Sivakumar K et al. Brain, 2005 Oct;128:2304-14; Schabhüttl M et al. J. Neurol., 2014 May;261:970-82; Karakaya M et al. Hum. Mutat., 2018 09;39:1284-1298). Functional studies of this alteration demonstrate reduced aminoacylation activity, substantial reductions in yeast viability, and altered cellular localization in transfected mouse motor neuron cell lines (Griffin LB et al. Hum. Mutat., 2014 Nov;35:1363-71; Antonellis A et al. J. Neurosci., 2006 Oct;26:10397-406). In addition to the clinical data presented in the literature, this alteration is absent in population-based cohorts in the Genome Aggregation Database (gnomAD) and predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2023

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 472 of the GARS protein (p.His472Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with peripheral neuropathy (PMID: 16014653, 24627108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410314). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GARS protein function. Experimental studies have shown that this missense change affects GARS function (PMID: 25168514). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Distal spinal muscular atrophy Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.94		Gain of solvent accessibility (P = 0.0584);
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.94

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: rs1060502838; hg19: chr7-30661064;