rs369898799

Variant names:

• chr7-30598843-C-T
• rs369898799
• ENST00000674815.1:c.-100C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000674815.1(GARS1):​c.-100C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,614,112 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: GARS1 ENST00000674815.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.185
• Publications: 1 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 7-30598843-C-T is Benign according to our data. Variant chr7-30598843-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 360002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000158 (24/152244) while in subpopulation SAS AF = 0.00186 (9/4834). AF 95% confidence interval is 0.000971. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.270C>T	p.Asp90Asp	synonymous_variant	Exon 2 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.108C>T	p.Asp36Asp	synonymous_variant	Exon 2 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000674815.1	c.-100C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.-100C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 18			ENSP00000502451.1
GARS1	ENST00000389266.8	c.270C>T	p.Asp90Asp	synonymous_variant	Exon 2 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.270C>T	p.Asp90Asp	synonymous_variant	Exon 2 of 17			ENSP00000502513.1
GARS1	ENST00000675693.1	c.102C>T	p.Asp34Asp	synonymous_variant	Exon 3 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.69C>T	p.Asp23Asp	synonymous_variant	Exon 2 of 17			ENSP00000502296.1
GARS1	ENST00000444666.6	n.270C>T		non_coding_transcript_exon_variant	Exon 2 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.270C>T		non_coding_transcript_exon_variant	Exon 2 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.270C>T		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.270C>T		non_coding_transcript_exon_variant	Exon 2 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.270C>T		non_coding_transcript_exon_variant	Exon 2 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*140C>T		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.270C>T		non_coding_transcript_exon_variant	Exon 2 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*140C>T		non_coding_transcript_exon_variant	Exon 3 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.270C>T		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.270C>T		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.270C>T		non_coding_transcript_exon_variant	Exon 2 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.270C>T		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.270C>T		non_coding_transcript_exon_variant	Exon 2 of 16			ENSP00000502681.1
GARS1	ENST00000674815.1	c.-100C>T		5_prime_UTR_variant	Exon 2 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.-100C>T		5_prime_UTR_variant	Exon 3 of 18			ENSP00000502451.1
GARS1	ENST00000675529.1	n.*140C>T		3_prime_UTR_variant	Exon 3 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*140C>T		3_prime_UTR_variant	Exon 3 of 19			ENSP00000501884.1
GARS1	ENST00000675810.1	c.223-1104C>T		intron_variant	Intron 1 of 15			ENSP00000502743.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152126 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: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000236 AC: 59 AN: 249516 AF XY: 0.000266

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000183 AC: 267 AN: 1461868 Hom.: 1 Cov.: 31 AF XY: 0.000216 AC XY: 157 AN XY: 727236

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44722

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00103 AC: 89 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1111998

Other (OTH) AF: 0.000397 AC: 24 AN: 60396

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74438

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68016

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000290 Hom.: 0

Bravo AF: 0.000140

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 25, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GARS1: BP4, BP7 -

not specified Benign:2

Mar 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 11, 2019

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. -

Charcot-Marie-Tooth disease Benign:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
BayesDel_noAF	Benign	-0.34
CADD	Benign	12
DANN	Benign	0.84
PhyloP100		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs369898799; hg19: chr7-30638459;