rs369894731

Variant names:

• chr7-30631490-G-A
• rs369894731
• NM_002047.4:c.1852G>A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_002047.4(GARS1):​c.1852G>A​(p.Val618Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,613,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:5
• Conservation: PhyloP100: 7.72

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21099356).
• BP6: Variant 7-30631490-G-A is Benign according to our data. Variant chr7-30631490-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216550.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000527 (8/151794) while in subpopulation NFE AF= 0.000118 (8/68002). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1852G>A	p.Val618Ile	missense_variant	Exon 15 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1690G>A	p.Val564Ile	missense_variant	Exon 15 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1852G>A	p.Val618Ile	missense_variant	Exon 15 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1852G>A	p.Val618Ile	missense_variant	Exon 15 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1750G>A	p.Val584Ile	missense_variant	Exon 14 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1684G>A	p.Val562Ile	missense_variant	Exon 16 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1651G>A	p.Val551Ile	missense_variant	Exon 15 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1483G>A	p.Val495Ile	missense_variant	Exon 15 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1483G>A	p.Val495Ile	missense_variant	Exon 16 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*273G>A		non_coding_transcript_exon_variant	Exon 16 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1566G>A		non_coding_transcript_exon_variant	Exon 16 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*952G>A		non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1190G>A		non_coding_transcript_exon_variant	Exon 16 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*125G>A		non_coding_transcript_exon_variant	Exon 14 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1722G>A		non_coding_transcript_exon_variant	Exon 16 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1794G>A		non_coding_transcript_exon_variant	Exon 17 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*797G>A		non_coding_transcript_exon_variant	Exon 15 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1303G>A		non_coding_transcript_exon_variant	Exon 15 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1141G>A		non_coding_transcript_exon_variant	Exon 16 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1284G>A		non_coding_transcript_exon_variant	Exon 15 of 17			ENSP00000501980.1
GARS1	ENST00000444666.6	n.*273G>A		3_prime_UTR_variant	Exon 16 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1566G>A		3_prime_UTR_variant	Exon 16 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*952G>A		3_prime_UTR_variant	Exon 16 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1190G>A		3_prime_UTR_variant	Exon 16 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*125G>A		3_prime_UTR_variant	Exon 14 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1722G>A		3_prime_UTR_variant	Exon 16 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1794G>A		3_prime_UTR_variant	Exon 17 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*797G>A		3_prime_UTR_variant	Exon 15 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1303G>A		3_prime_UTR_variant	Exon 15 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1141G>A		3_prime_UTR_variant	Exon 16 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1284G>A		3_prime_UTR_variant	Exon 15 of 17			ENSP00000501980.1
GARS1	ENST00000675859.1	n.*83-757G>A		intron_variant	Intron 13 of 14			ENSP00000502033.1
GARS1	ENST00000676403.1	n.1810-757G>A		intron_variant	Intron 14 of 15			ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151794 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000843 AC: 21 AN: 249202 Hom.: 0 AF XY: 0.000104 AC XY: 14 AN XY: 135242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000602 AC: 88 AN: 1461458 Hom.: 0 Cov.: 30 AF XY: 0.0000660 AC XY: 48 AN XY: 727032

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: 0.0000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000693

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151794 Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4 AN XY: 74098

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000494 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000108 AC: 13

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Apr 18, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 11, 2023

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging. -

Dec 18, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tip-toe gait Pathogenic:1

-

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 618 of the GARS protein (p.Val618Ile). This variant is present in population databases (rs369894731, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 216550). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GARS protein function with a negative predictive value of 95%. 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. -

not specified Benign:1

Aug 03, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Distal spinal muscular atrophy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 2D Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Neuronopathy, distal hereditary motor, type 5A Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.050
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.49	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.44	N
REVEL	Uncertain	0.37
Sift	Benign	0.27	T
Sift4G	Benign	0.60	T
Polyphen		0.049	B
Vest4		0.20
MVP		0.68
MPC		0.36
ClinPred		0.084	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs369894731; hg19: chr7-30671106;