rs192443850

Variant names:

• chr7-30615964-A-G
• rs192443850
• NM_002047.4:c.1100A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002047.4(GARS1):​c.1100A>G​(p.Asn367Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,614,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:7
• Conservation: PhyloP100: 1.49

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017736435).
• BP6: Variant 7-30615964-A-G is Benign according to our data. Variant chr7-30615964-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 360011.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000203 (31/152338) while in subpopulation NFE AF= 0.000426 (29/68032). AF 95% confidence interval is 0.000304. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1100A>G	p.Asn367Ser	missense_variant	Exon 9 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.938A>G	p.Asn313Ser	missense_variant	Exon 9 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1100A>G	p.Asn367Ser	missense_variant	Exon 9 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1100A>G	p.Asn367Ser	missense_variant	Exon 9 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.998A>G	p.Asn333Ser	missense_variant	Exon 8 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.932A>G	p.Asn311Ser	missense_variant	Exon 10 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.899A>G	p.Asn300Ser	missense_variant	Exon 9 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.731A>G	p.Asn244Ser	missense_variant	Exon 9 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.731A>G	p.Asn244Ser	missense_variant	Exon 10 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1100A>G		non_coding_transcript_exon_variant	Exon 9 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*814A>G		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*200A>G		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*438A>G		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1100A>G		non_coding_transcript_exon_variant	Exon 9 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*970A>G		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1100A>G		non_coding_transcript_exon_variant	Exon 9 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1042A>G		non_coding_transcript_exon_variant	Exon 11 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*45A>G		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*551A>G		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*389A>G		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*532A>G		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1100A>G		non_coding_transcript_exon_variant	Exon 9 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*814A>G		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*200A>G		3_prime_UTR_variant	Exon 10 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*438A>G		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*970A>G		3_prime_UTR_variant	Exon 10 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1042A>G		3_prime_UTR_variant	Exon 11 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*45A>G		3_prime_UTR_variant	Exon 9 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*551A>G		3_prime_UTR_variant	Exon 9 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*389A>G		3_prime_UTR_variant	Exon 10 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*532A>G		3_prime_UTR_variant	Exon 9 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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: 0.000426

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000248 AC: 62 AN: 249570 Hom.: 0 AF XY: 0.000207 AC XY: 28 AN XY: 135402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000538

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000252 AC: 369 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 156 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000315

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000203 AC: 31 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74504

Gnomad4 AFR AF: 0.0000481

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: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000311 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000363 AC: 3

ExAC AF: 0.000289 AC: 35

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Dec 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with Charcot-Marie-Tooth disease in published literature; however detailed clinical information and inheritance were not provided (PMID: 25614874, 32376792); Identified in a patient with sporadic amyotrophic lateral sclerosis in the published literature who also had a variant in another gene that may have been responsible for the phenotype (PMID: 27790088); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25168514, 26138142, 26503042, 25614874, 32376792, 27790088) -

Feb 07, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GARS1 c.1100A>G; p.Asn367Ser variant (rs192443850), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 360011). This variant is found in the general population with an overall allele frequency of 0.025% (69/280970 alleles) in the Genome Aggregation Database. The asparagine at codon 367 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.263). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GARS1: BP4, BS2 -

Charcot-Marie-Tooth disease Pathogenic:1

-

Inherited Neuropathy Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

not specified Benign:1

Oct 01, 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 2 Benign:1

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GARS1-related disorder Benign:1

Dec 22, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	0.068
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.44
DEOGEN2	Benign	0.097	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.95	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.040
MVP		0.30
MPC		0.28
ClinPred		0.016	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.042
gMVP		0.25

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: rs192443850; hg19: chr7-30655580;