chr7-30609596-T-C

Variant names:

• chr7-30609596-T-C
• rs7808770
• NM_002047.4:c.747T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002047.4(GARS1):​c.747T>C​(p.Tyr249Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,613,054 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (62 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (59 hom.)
• Consequence: GARS1 NM_002047.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.438
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 7-30609596-T-C is Benign according to our data. Variant chr7-30609596-T-C is described in ClinVar as [Benign]. Clinvar id is 258538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.438 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.747T>C	p.Tyr249Tyr	synonymous_variant	Exon 7 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.585T>C	p.Tyr195Tyr	synonymous_variant	Exon 7 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.747T>C	p.Tyr249Tyr	synonymous_variant	Exon 7 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.747T>C	p.Tyr249Tyr	synonymous_variant	Exon 7 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.645T>C	p.Tyr215Tyr	synonymous_variant	Exon 6 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.579T>C	p.Tyr193Tyr	synonymous_variant	Exon 8 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.546T>C	p.Tyr182Tyr	synonymous_variant	Exon 7 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.378T>C	p.Tyr126Tyr	synonymous_variant	Exon 7 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.378T>C	p.Tyr126Tyr	synonymous_variant	Exon 8 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.747T>C		non_coding_transcript_exon_variant	Exon 7 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*461T>C		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.747T>C		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*85T>C		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.747T>C		non_coding_transcript_exon_variant	Exon 7 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*617T>C		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.747T>C		non_coding_transcript_exon_variant	Exon 7 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*689T>C		non_coding_transcript_exon_variant	Exon 9 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.747T>C		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*198T>C		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*36T>C		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*179T>C		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.747T>C		non_coding_transcript_exon_variant	Exon 7 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*461T>C		3_prime_UTR_variant	Exon 8 of 18			ENSP00000502408.1
GARS1	ENST00000674737.1	n.*85T>C		3_prime_UTR_variant	Exon 8 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*617T>C		3_prime_UTR_variant	Exon 8 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*689T>C		3_prime_UTR_variant	Exon 9 of 19			ENSP00000501884.1
GARS1	ENST00000676164.1	n.*198T>C		3_prime_UTR_variant	Exon 7 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*36T>C		3_prime_UTR_variant	Exon 8 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*179T>C		3_prime_UTR_variant	Exon 7 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2224 AN: 152206 Hom.: 62 Cov.: 33

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00397 AC: 989 AN: 249406 AF XY: 0.00282

Gnomad AFR exome AF: 0.0546

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00159 AC: 2319 AN: 1460730 Hom.: 59 Cov.: 30 AF XY: 0.00140 AC XY: 1019 AN XY: 726762

African (AFR) AF: 0.0540 AC: 1804 AN: 33428

American (AMR) AF: 0.00338 AC: 151 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5762

European-Non Finnish (NFE) AF: 0.000117 AC: 130 AN: 1111200

Other (OTH) AF: 0.00348 AC: 210 AN: 60358

GnomAD4 genome AF: 0.0146 AC: 2228 AN: 152324 Hom.: 62 Cov.: 33 AF XY: 0.0140 AC XY: 1042 AN XY: 74496

African (AFR) AF: 0.0504 AC: 2097 AN: 41578

American (AMR) AF: 0.00621 AC: 95 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68014

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00723 Hom.: 18

Bravo AF: 0.0169

Asia WGS AF: 0.00289 AC: 10 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 28, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 31, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Benign:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: 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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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: 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. -

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	-0.51
CADD	Benign	4.8
DANN	Benign	0.54
PhyloP100		0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs7808770; hg19: chr7-30649212;