7-30633729-C-T

Variant names:

• chr7-30633729-C-T
• rs2240401
• NM_002047.4:c.2095-6C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002047.4(GARS1):​c.2095-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,612,332 control chromosomes in the GnomAD database, including 303,617 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (21504 hom., cov: 30)
  • Exomes 𝑓: 0.61 (282113 hom.)
• Consequence: GARS1 NM_002047.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002226
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.97

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-30633729-C-T is Benign according to our data. Variant chr7-30633729-C-T is described in ClinVar as [Benign]. Clinvar id is 258536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30633729-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.2095-6C>T		splice_region_variant, intron_variant	Intron 16 of 16	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1933-6C>T		splice_region_variant, intron_variant	Intron 16 of 16		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.2095-6C>T		splice_region_variant, intron_variant	Intron 16 of 16	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.2113-6C>T		splice_region_variant, intron_variant	Intron 16 of 16			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1993-6C>T		splice_region_variant, intron_variant	Intron 15 of 15			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1927-6C>T		splice_region_variant, intron_variant	Intron 17 of 17			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1894-6C>T		splice_region_variant, intron_variant	Intron 16 of 16			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1726-6C>T		splice_region_variant, intron_variant	Intron 16 of 16			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1726-6C>T		splice_region_variant, intron_variant	Intron 17 of 17			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*516-6C>T		splice_region_variant, intron_variant	Intron 17 of 17	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1809-6C>T		splice_region_variant, intron_variant	Intron 17 of 17			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*1900-6C>T		splice_region_variant, intron_variant	Intron 16 of 16			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1433-6C>T		splice_region_variant, intron_variant	Intron 17 of 17			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*368-6C>T		splice_region_variant, intron_variant	Intron 15 of 15			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1965-6C>T		splice_region_variant, intron_variant	Intron 17 of 17			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*274-6C>T		splice_region_variant, intron_variant	Intron 14 of 14			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*2037-6C>T		splice_region_variant, intron_variant	Intron 18 of 18			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*1040-6C>T		splice_region_variant, intron_variant	Intron 16 of 16			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1546-6C>T		splice_region_variant, intron_variant	Intron 16 of 16			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1384-6C>T		splice_region_variant, intron_variant	Intron 17 of 17			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1527-6C>T		splice_region_variant, intron_variant	Intron 16 of 16			ENSP00000501980.1
GARS1	ENST00000676403.1	n.*180-6C>T		splice_region_variant, intron_variant	Intron 15 of 15			ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.487 AC: 73957 AN: 151770 Hom.: 21507 Cov.: 30

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.682

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.521

GnomAD3 exomes AF: 0.560 AC: 139586 AN: 249068 Hom.: 41588 AF XY: 0.563 AC XY: 76049 AN XY: 135166

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.559

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.488

Gnomad SAS exome AF: 0.416

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.592

GnomAD4 exome AF: 0.613 AC: 894881 AN: 1460442 Hom.: 282113 Cov.: 42 AF XY: 0.608 AC XY: 441967 AN XY: 726596

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.553

Gnomad4 ASJ exome AF: 0.669

Gnomad4 EAS exome AF: 0.451

Gnomad4 SAS exome AF: 0.421

Gnomad4 FIN exome AF: 0.638

Gnomad4 NFE exome AF: 0.650

Gnomad4 OTH exome AF: 0.579

GnomAD4 genome AF: 0.487 AC: 73958 AN: 151890 Hom.: 21504 Cov.: 30 AF XY: 0.484 AC XY: 35937 AN XY: 74202

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.539

Gnomad4 ASJ AF: 0.682

Gnomad4 EAS AF: 0.477

Gnomad4 SAS AF: 0.418

Gnomad4 FIN AF: 0.643

Gnomad4 NFE AF: 0.647

Gnomad4 OTH AF: 0.519

Alfa AF: 0.612 Hom.: 45437

Bravo AF: 0.465

Asia WGS AF: 0.413 AC: 1438 AN: 3478

EpiCase AF: 0.644

EpiControl AF: 0.634

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2021	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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. -

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

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Charcot-Marie-Tooth disease Benign:1

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. -

Spinal muscular atrophy, infantile, James type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.11
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0020
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: rs2240401; hg19: chr7-30673345; COSMIC: COSV66828329; COSMIC: COSV66828329;