7-30633785-A-G

Variant names:

• chr7-30633785-A-G
• rs4593
• NM_002047.4:c.2145A>G

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.2145A>G​(p.Thr715Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0399 in 1,608,902 control chromosomes in the GnomAD database, including 2,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (1155 hom., cov: 31)
  • Exomes 𝑓: 0.035 (1684 hom.)
• Consequence: GARS1 NM_002047.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.72
• Publications: 10 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=-0.65).
• BP6: Variant 7-30633785-A-G is Benign according to our data. Variant chr7-30633785-A-G is described in ClinVar as Benign. ClinVar VariationId is 137443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002047.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	NM_002047.4	MANE Select	c.2145A>G	p.Thr715Thr	synonymous	Exon 17 of 17	NP_002038.2
	GARS1	NM_001316772.1		c.1983A>G	p.Thr661Thr	synonymous	Exon 17 of 17	NP_001303701.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000389266.8	TSL:1 MANE Select	c.2145A>G	p.Thr715Thr	synonymous	Exon 17 of 17	ENSP00000373918.3
	GARS1	ENST00000675651.1		c.2163A>G	p.Thr721Thr	synonymous	Exon 17 of 17	ENSP00000502513.1
	GARS1	ENST00000675810.1		c.2043A>G	p.Thr681Thr	synonymous	Exon 16 of 16	ENSP00000502743.1

Frequencies

GnomAD3 genomes AF: 0.0842 AC: 12779 AN: 151840 Hom.: 1146 Cov.: 31

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0512

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.00479

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0680

GnomAD2 exomes AF: 0.0362 AC: 9044 AN: 249520 AF XY: 0.0329

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.0280

Gnomad ASJ exome AF: 0.0255

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0318

Gnomad OTH exome AF: 0.0340

GnomAD4 exome AF: 0.0353 AC: 51393 AN: 1456946 Hom.: 1684 Cov.: 42 AF XY: 0.0340 AC XY: 24607 AN XY: 724742

African (AFR) AF: 0.234 AC: 7802 AN: 33334

American (AMR) AF: 0.0317 AC: 1411 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.0243 AC: 630 AN: 25952

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39346

South Asian (SAS) AF: 0.00831 AC: 716 AN: 86204

European-Finnish (FIN) AF: 0.0140 AC: 740 AN: 52924

Middle Eastern (MID) AF: 0.0407 AC: 234 AN: 5748

European-Non Finnish (NFE) AF: 0.0335 AC: 37195 AN: 1108834

Other (OTH) AF: 0.0443 AC: 2659 AN: 60086

GnomAD4 genome AF: 0.0844 AC: 12819 AN: 151956 Hom.: 1155 Cov.: 31 AF XY: 0.0820 AC XY: 6090 AN XY: 74292

African (AFR) AF: 0.224 AC: 9283 AN: 41416

American (AMR) AF: 0.0510 AC: 778 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3470

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5152

South Asian (SAS) AF: 0.00501 AC: 24 AN: 4794

European-Finnish (FIN) AF: 0.0123 AC: 130 AN: 10574

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

European-Non Finnish (NFE) AF: 0.0325 AC: 2211 AN: 67974

Other (OTH) AF: 0.0673 AC: 142 AN: 2110

Alfa AF: 0.0414 Hom.: 173

Bravo AF: 0.0945

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.0358

EpiControl AF: 0.0337

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Charcot-Marie-Tooth disease type 2D (1)
-	-	1	Distal spinal muscular atrophy (1)
-	-	1	Neuronopathy, distal hereditary motor, type 5A (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.57
DANN	Benign	0.70
PhyloP100		-1.7
Mutation Taster		=98/2	polymorphism (auto)

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: rs4593; hg19: chr7-30673401; COSMIC: COSV66828907; COSMIC: COSV66828907;