7-30633729-C-T

Variant names:

• chr7-30633729-C-T
• rs2240401
• NM_002047.4:c.2095-6C>T

Variant summary

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

The ENST00000389266.8(GARS1):​c.2095-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.601 in 1,612,332 control chromosomes in the GnomAD database, including 303,617 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (21504 hom., cov: 30)
  • Exomes 𝑓: 0.61 (282113 hom.)
• Consequence: GARS1 ENST00000389266.8 splice_region, intron
• Scores: Splicing: ADA: 0.00002226
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.97
• Publications: 18 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=-0.83).
• BP6: Variant 7-30633729-C-T is Benign according to our data. Variant chr7-30633729-C-T is described in ClinVar as Benign. ClinVar VariationId is 258536.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: ENST00000389266.8. 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.2095-6C>T		splice_region intron	N/A	NP_002038.2
	GARS1	NM_001316772.1		c.1933-6C>T		splice_region 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.2095-6C>T		splice_region intron	N/A	ENSP00000373918.3
	GARS1	ENST00000675651.1		c.2113-6C>T		splice_region intron	N/A	ENSP00000502513.1
	GARS1	ENST00000675810.1		c.1993-6C>T		splice_region intron	N/A	ENSP00000502743.1

Frequencies

GnomAD3 genomes AF: 0.487 AC: 73957 AN: 151770 Hom.: 21507 Cov.: 30

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.682

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.521

GnomAD2 exomes AF: 0.560 AC: 139586 AN: 249068 AF XY: 0.563

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.559

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.488

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.592

GnomAD4 exome AF: 0.613 AC: 894881 AN: 1460442 Hom.: 282113 Cov.: 42 AF XY: 0.608 AC XY: 441967 AN XY: 726596

African (AFR) AF: 0.130 AC: 4338 AN: 33460

American (AMR) AF: 0.553 AC: 24727 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 17451 AN: 26102

East Asian (EAS) AF: 0.451 AC: 17904 AN: 39680

South Asian (SAS) AF: 0.421 AC: 36319 AN: 86210

European-Finnish (FIN) AF: 0.638 AC: 33964 AN: 53212

Middle Eastern (MID) AF: 0.549 AC: 3163 AN: 5764

European-Non Finnish (NFE) AF: 0.650 AC: 722066 AN: 1110954

Other (OTH) AF: 0.579 AC: 34949 AN: 60358

GnomAD4 genome AF: 0.487 AC: 73958 AN: 151890 Hom.: 21504 Cov.: 30 AF XY: 0.484 AC XY: 35937 AN XY: 74202

African (AFR) AF: 0.154 AC: 6383 AN: 41446

American (AMR) AF: 0.539 AC: 8214 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 2365 AN: 3466

East Asian (EAS) AF: 0.477 AC: 2452 AN: 5136

South Asian (SAS) AF: 0.418 AC: 2012 AN: 4810

European-Finnish (FIN) AF: 0.643 AC: 6768 AN: 10528

Middle Eastern (MID) AF: 0.562 AC: 164 AN: 292

European-Non Finnish (NFE) AF: 0.647 AC: 43958 AN: 67946

Other (OTH) AF: 0.519 AC: 1092 AN: 2106

Alfa AF: 0.595 Hom.: 58181

Bravo AF: 0.465

Asia WGS AF: 0.413 AC: 1438 AN: 3478

EpiCase AF: 0.644

EpiControl AF: 0.634

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.11
DANN	Benign	0.48
PhyloP100		-2.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0020
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: rs2240401; hg19: chr7-30673345; COSMIC: COSV66828329; COSMIC: COSV66828329;