rs369898799

Positions:

• chr7-30598843-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000674815(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 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.185

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 -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

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

Ensembl

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

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

GnomAD3 exomes AF: 0.000236 AC: 59 AN: 249516 Hom.: 0 AF XY: 0.000266 AC XY: 36 AN XY: 135390

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 SAS exome AF: 0.00105

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00103

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000116

Gnomad4 OTH exome AF: 0.000397

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000474

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 11, 2019	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 28, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Distal spinal muscular atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs369898799; hg19: chr7-30638459;