rs14270

Variant names:

• chr7-30631471-T-C
• rs14270
• NM_002047.4:c.1833T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-30631471-T-C
• chr7-30631471-T-A

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.1833T>C​(p.Val611Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,613,064 control chromosomes in the GnomAD database, including 912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (169 hom., cov: 32)
  • Exomes 𝑓: 0.030 (743 hom.)
• Consequence: GARS1 NM_002047.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.932
• Publications: 6 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• neuronopathy, distal hereditary motor, type 5A

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Illumina, Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.87).
• BP6: Variant 7-30631471-T-C is Benign according to our data. Variant chr7-30631471-T-C is described in ClinVar as Benign. ClinVar VariationId is 137442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.932 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0676 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.1833T>C	p.Val611Val	synonymous	Exon 15 of 17	NP_002038.2	P41250-1
	GARS1	NM_001316772.1		c.1671T>C	p.Val557Val	synonymous	Exon 15 of 17	NP_001303701.1	P41250-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000389266.8	TSL:1 MANE Select	c.1833T>C	p.Val611Val	synonymous	Exon 15 of 17	ENSP00000373918.3	P41250-1
	GARS1	ENST00000675651.1		c.1833T>C	p.Val611Val	synonymous	Exon 15 of 17	ENSP00000502513.1	A0A6Q8PGZ8
	GARS1	ENST00000675810.1		c.1731T>C	p.Val577Val	synonymous	Exon 14 of 16	ENSP00000502743.1	A0A6Q8PHH9

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6033 AN: 152196 Hom.: 165 Cov.: 32

Gnomad AFR AF: 0.0696

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0317

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0249 AC: 6193 AN: 249142 AF XY: 0.0244

Gnomad AFR exome AF: 0.0681

Gnomad AMR exome AF: 0.0199

Gnomad ASJ exome AF: 0.0255

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.0312

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0300 AC: 43884 AN: 1460750 Hom.: 743 Cov.: 30 AF XY: 0.0294 AC XY: 21381 AN XY: 726706

African (AFR) AF: 0.0722 AC: 2414 AN: 33440

American (AMR) AF: 0.0222 AC: 994 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 624 AN: 26120

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39668

South Asian (SAS) AF: 0.00758 AC: 654 AN: 86250

European-Finnish (FIN) AF: 0.0138 AC: 738 AN: 53376

Middle Eastern (MID) AF: 0.0314 AC: 181 AN: 5764

European-Non Finnish (NFE) AF: 0.0327 AC: 36331 AN: 1111066

Other (OTH) AF: 0.0322 AC: 1944 AN: 60350

GnomAD4 genome AF: 0.0397 AC: 6048 AN: 152314 Hom.: 169 Cov.: 32 AF XY: 0.0382 AC XY: 2848 AN XY: 74470

African (AFR) AF: 0.0697 AC: 2897 AN: 41562

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: 5186

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4822

European-Finnish (FIN) AF: 0.0123 AC: 130 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0317 AC: 2160 AN: 68042

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

Alfa AF: 0.0359 Hom.: 129

Bravo AF: 0.0434

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0350

EpiControl AF: 0.0330

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	-0.87
CADD	Benign	3.9
DANN	Benign	0.62
PhyloP100		-0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs14270; hg19: chr7-30671087; COSMIC: COSV66828208; COSMIC: COSV66828208;