chr7-30622471-T-C

Variant names:

• chr7-30622471-T-C
• rs75855065
• NM_002047.4:c.1613+9T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002047.4(GARS1):​c.1613+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 1,613,776 control chromosomes in the GnomAD database, including 1,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (219 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1255 hom.)
• Consequence: GARS1 NM_002047.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0470
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 7-30622471-T-C is Benign according to our data. Variant chr7-30622471-T-C is described in ClinVar as Benign. ClinVar VariationId is 137441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1613+9T>C		intron_variant	Intron 12 of 16	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1451+9T>C		intron_variant	Intron 12 of 16		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1613+9T>C		intron_variant	Intron 12 of 16	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1613+9T>C		intron_variant	Intron 12 of 16			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1511+9T>C		intron_variant	Intron 11 of 15			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1445+9T>C		intron_variant	Intron 13 of 17			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1412+9T>C		intron_variant	Intron 12 of 16			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1244+9T>C		intron_variant	Intron 12 of 16			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1244+9T>C		intron_variant	Intron 13 of 17			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1613+9T>C		intron_variant	Intron 12 of 17	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1327+9T>C		intron_variant	Intron 13 of 17			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*713+9T>C		intron_variant	Intron 13 of 16			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*951+9T>C		intron_variant	Intron 13 of 17			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1613+9T>C		intron_variant	Intron 12 of 15			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1483+9T>C		intron_variant	Intron 13 of 17			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1613+9T>C		intron_variant	Intron 12 of 14			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1555+9T>C		intron_variant	Intron 14 of 18			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*558+9T>C		intron_variant	Intron 12 of 16			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1064+9T>C		intron_variant	Intron 12 of 16			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*902+9T>C		intron_variant	Intron 13 of 17			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1045+9T>C		intron_variant	Intron 12 of 16			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1613+9T>C		intron_variant	Intron 12 of 15			ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 7167 AN: 152114 Hom.: 215 Cov.: 32

Gnomad AFR AF: 0.0736

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0436

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0431

GnomAD2 exomes AF: 0.0333 AC: 8301 AN: 249490 AF XY: 0.0334

Gnomad AFR exome AF: 0.0716

Gnomad AMR exome AF: 0.0257

Gnomad ASJ exome AF: 0.0467

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.0424

Gnomad OTH exome AF: 0.0362

GnomAD4 exome AF: 0.0400 AC: 58425 AN: 1461544 Hom.: 1255 Cov.: 31 AF XY: 0.0393 AC XY: 28564 AN XY: 727108

African (AFR) AF: 0.0762 AC: 2552 AN: 33470

American (AMR) AF: 0.0283 AC: 1265 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 1159 AN: 26126

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39676

South Asian (SAS) AF: 0.0151 AC: 1301 AN: 86252

European-Finnish (FIN) AF: 0.0172 AC: 920 AN: 53396

Middle Eastern (MID) AF: 0.0508 AC: 293 AN: 5766

European-Non Finnish (NFE) AF: 0.0436 AC: 48419 AN: 1111770

Other (OTH) AF: 0.0416 AC: 2511 AN: 60366

GnomAD4 genome AF: 0.0472 AC: 7182 AN: 152232 Hom.: 219 Cov.: 32 AF XY: 0.0454 AC XY: 3378 AN XY: 74436

African (AFR) AF: 0.0737 AC: 3063 AN: 41536

American (AMR) AF: 0.0436 AC: 667 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0131 AC: 63 AN: 4822

European-Finnish (FIN) AF: 0.0155 AC: 164 AN: 10614

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0415 AC: 2824 AN: 68002

Other (OTH) AF: 0.0422 AC: 89 AN: 2110

Alfa AF: 0.0466 Hom.: 101

Bravo AF: 0.0514

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Apr 03, 2014

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

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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:2

Sep 08, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 29, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

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

Feb 03, 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
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.7
DANN	Benign	0.75
PhyloP100		-0.047
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs75855065; hg19: chr7-30662087;