7-30594932-C-T

Variant names:

• chr7-30594932-C-T
• rs62636572
• ENST00000674815:c.-168C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001316772.1(GARS1):​c.-152C>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 0.0139 in 1,591,090 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 33)
  • Exomes 𝑓: 0.014 (172 hom.)
• Consequence: GARS1 NM_001316772.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.13

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-DT (HGNC:48951): (GARS1 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019283891).
• BP6: Variant 7-30594932-C-T is Benign according to our data. Variant chr7-30594932-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30594932-C-T is described in Lovd as [Benign]. Variant chr7-30594932-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0124 (1882/152304) while in subpopulation AMR AF= 0.0169 (258/15296). AF 95% confidence interval is 0.0152. There are 12 homozygotes in gnomad4. There are 1010 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1882 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.-152C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17		NP_001303701.1
GARS1	NM_001316772.1	c.-152C>T		5_prime_UTR_variant	Exon 1 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000674815	c.-168C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 17			ENSP00000502799.1
GARS1	ENST00000674851	c.-204C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 18			ENSP00000502451.1
GARS1	ENST00000389266.8	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 18			ENSP00000502174.1
GARS1	ENST00000674815	c.-168C>T		5_prime_UTR_variant	Exon 1 of 17			ENSP00000502799.1
GARS1	ENST00000674851	c.-204C>T		5_prime_UTR_variant	Exon 1 of 18			ENSP00000502451.1
GARS1	ENST00000675051.1	c.22-3864C>T		intron_variant	Intron 1 of 16			ENSP00000502296.1
GARS1	ENST00000444666.6	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 16			ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1883 AN: 152186 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.0116 AC: 2454 AN: 210896 Hom.: 25 AF XY: 0.0114 AC XY: 1330 AN XY: 117096

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00293

Gnomad FIN exome AF: 0.0302

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0193

GnomAD4 exome AF: 0.0141 AC: 20291 AN: 1438786 Hom.: 172 Cov.: 30 AF XY: 0.0137 AC XY: 9830 AN XY: 715340

Gnomad4 AFR exome AF: 0.00216

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.00360

Gnomad4 FIN exome AF: 0.0305

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0124 AC: 1882 AN: 152304 Hom.: 12 Cov.: 33 AF XY: 0.0136 AC XY: 1010 AN XY: 74488

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00310

Gnomad4 FIN AF: 0.0372

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0143 Hom.: 20

Bravo AF: 0.0113

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00251 AC: 10

ESP6500EA AF: 0.0139 AC: 113

ExAC AF: 0.0104 AC: 1241

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 24, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

Feb 29, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: 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

- -

Mar 03, 2015

GeneDx

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 12, 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

Jan 30, 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 12, 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 12, 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	0.13
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.15
DANN	Benign	0.92
DEOGEN2	Benign	0.074	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.22
Sift	Benign	0.59	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.059
MPC		0.35
ClinPred		0.020	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.019
gMVP		0.37

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: rs62636572; hg19: chr7-30634548; COSMIC: COSV66829127; COSMIC: COSV66829127;