NM_002047.4:c.659-43C>A

Variant names:

• chr7-30603453-C-A
• rs1558064
• NM_002047.4:c.659-43C>A

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.659-43C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 1,482,540 control chromosomes in the GnomAD database, including 277,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (21416 hom., cov: 32)
  • Exomes 𝑓: 0.61 (255973 hom.)
• Consequence: GARS1 NM_002047.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.151
• Publications: 12 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=-0.82).
• BP6: Variant 7-30603453-C-A is Benign according to our data. Variant chr7-30603453-C-A is described in ClinVar as Benign. ClinVar VariationId is 258537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.642 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	NM_002047.4	MANE Select	c.659-43C>A		intron	N/A	NP_002038.2
	GARS1	NM_001316772.1		c.497-43C>A		intron	N/A	NP_001303701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000389266.8	TSL:1 MANE Select	c.659-43C>A		intron	N/A	ENSP00000373918.3
	GARS1	ENST00000675651.1		c.659-43C>A		intron	N/A	ENSP00000502513.1
	GARS1	ENST00000675810.1		c.557-43C>A		intron	N/A	ENSP00000502743.1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73395 AN: 151924 Hom.: 21419 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.606

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.514

GnomAD2 exomes AF: 0.559 AC: 138079 AN: 246982 AF XY: 0.561

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.557

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.488

Gnomad FIN exome AF: 0.638

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.589

GnomAD4 exome AF: 0.611 AC: 812985 AN: 1330496 Hom.: 255973 Cov.: 20 AF XY: 0.606 AC XY: 405808 AN XY: 669240

African (AFR) AF: 0.119 AC: 3671 AN: 30766

American (AMR) AF: 0.552 AC: 24482 AN: 44374

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 16949 AN: 25350

East Asian (EAS) AF: 0.451 AC: 17605 AN: 39050

South Asian (SAS) AF: 0.422 AC: 35202 AN: 83482

European-Finnish (FIN) AF: 0.638 AC: 33822 AN: 53048

Middle Eastern (MID) AF: 0.557 AC: 2413 AN: 4336

European-Non Finnish (NFE) AF: 0.650 AC: 646487 AN: 994172

Other (OTH) AF: 0.579 AC: 32354 AN: 55918

GnomAD4 genome AF: 0.483 AC: 73392 AN: 152044 Hom.: 21416 Cov.: 32 AF XY: 0.481 AC XY: 35713 AN XY: 74292

African (AFR) AF: 0.141 AC: 5837 AN: 41504

American (AMR) AF: 0.534 AC: 8148 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2369 AN: 3470

East Asian (EAS) AF: 0.476 AC: 2457 AN: 5160

South Asian (SAS) AF: 0.421 AC: 2028 AN: 4820

European-Finnish (FIN) AF: 0.644 AC: 6797 AN: 10562

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 43962 AN: 67942

Other (OTH) AF: 0.512 AC: 1081 AN: 2112

Alfa AF: 0.510 Hom.: 3368

Bravo AF: 0.460

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.1
DANN	Benign	0.53
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs1558064; hg19: chr7-30643069; COSMIC: COSV66828323; COSMIC: COSV66828323;