rs11553502

Variant names:

• chr7-30615926-T-C
• rs11553502
• NM_002047.4:c.1062T>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.1062T>C​(p.Phe354Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.0311 in 1,614,144 control chromosomes in the GnomAD database, including 913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (166 hom., cov: 33)
  • Exomes 𝑓: 0.030 (747 hom.)
• Consequence: GARS1 NM_002047.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 5.07
• 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=-0.53).
• BP6: Variant 7-30615926-T-C is Benign according to our data. Variant chr7-30615926-T-C is described in ClinVar as Benign. ClinVar VariationId is 137440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0675 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.1062T>C	p.Phe354Phe	synonymous	Exon 9 of 17	NP_002038.2
	GARS1	NM_001316772.1		c.900T>C	p.Phe300Phe	synonymous	Exon 9 of 17	NP_001303701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000389266.8	TSL:1 MANE Select	c.1062T>C	p.Phe354Phe	synonymous	Exon 9 of 17	ENSP00000373918.3
	GARS1	ENST00000675651.1		c.1062T>C	p.Phe354Phe	synonymous	Exon 9 of 17	ENSP00000502513.1
	GARS1	ENST00000675810.1		c.960T>C	p.Phe320Phe	synonymous	Exon 8 of 16	ENSP00000502743.1

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6030 AN: 152176 Hom.: 162 Cov.: 33

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0318

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0249 AC: 6209 AN: 249552 AF XY: 0.0244

Gnomad AFR exome AF: 0.0680

Gnomad AMR exome AF: 0.0199

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0312

Gnomad OTH exome AF: 0.0272

GnomAD4 exome AF: 0.0302 AC: 44205 AN: 1461850 Hom.: 747 Cov.: 32 AF XY: 0.0296 AC XY: 21520 AN XY: 727230

African (AFR) AF: 0.0725 AC: 2426 AN: 33478

American (AMR) AF: 0.0223 AC: 996 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0240 AC: 626 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.00762 AC: 657 AN: 86258

European-Finnish (FIN) AF: 0.0139 AC: 741 AN: 53418

Middle Eastern (MID) AF: 0.0314 AC: 181 AN: 5768

European-Non Finnish (NFE) AF: 0.0329 AC: 36617 AN: 1111976

Other (OTH) AF: 0.0324 AC: 1957 AN: 60396

GnomAD4 genome AF: 0.0397 AC: 6044 AN: 152294 Hom.: 166 Cov.: 33 AF XY: 0.0383 AC XY: 2852 AN XY: 74474

African (AFR) AF: 0.0696 AC: 2892 AN: 41540

American (AMR) AF: 0.0343 AC: 524 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00476 AC: 23 AN: 4828

European-Finnish (FIN) AF: 0.0122 AC: 130 AN: 10614

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0318 AC: 2161 AN: 68028

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0358 Hom.: 189

Bravo AF: 0.0433

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0349

EpiControl AF: 0.0330

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.74
PhyloP100		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	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: rs11553502; hg19: chr7-30655542;