rs118002895

chr7-30628515-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002047.4(GARS1):c.1700-45T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,325,674 control chromosomes in the GnomAD database, including 664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (75 hom., cov: 32)
  • Exomes 𝑓: 0.029 (589 hom.)
• Consequence: GARS1 NM_002047.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.626

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 7-30628515-T-C is Benign according to our data. Variant chr7-30628515-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 258533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30628515-T-C is described in Lovd as [Benign]. Variant chr7-30628515-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0226 (3441/152330) while in subpopulation NFE AF= 0.0323 (2196/68028). AF 95% confidence interval is 0.0312. There are 75 homozygotes in gnomad4. There are 1718 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3443 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GARS1	NM_002047.4	c.1700-45T>C		intron_variant		ENST00000389266.8
GARS1	NM_001316772.1	c.1538-45T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GARS1	ENST00000389266.8	c.1700-45T>C		intron_variant		1	NM_002047.4	P2

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3443 AN: 152212 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0598

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0244 AC: 6089 AN: 249392 Hom.: 131 AF XY: 0.0250 AC XY: 3383 AN XY: 135302

Gnomad AFR exome AF: 0.00459

Gnomad AMR exome AF: 0.00964

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0172

Gnomad FIN exome AF: 0.0551

Gnomad NFE exome AF: 0.0317

Gnomad OTH exome AF: 0.0213

GnomAD4 exome AF: 0.0289 AC: 33960 AN: 1173344 Hom.: 589 Cov.: 15 AF XY: 0.0290 AC XY: 17339 AN XY: 598030

Gnomad4 AFR exome AF: 0.00405

Gnomad4 AMR exome AF: 0.00957

Gnomad4 ASJ exome AF: 0.0268

Gnomad4 EAS exome AF: 0.0000530

Gnomad4 SAS exome AF: 0.0186

Gnomad4 FIN exome AF: 0.0530

Gnomad4 NFE exome AF: 0.0318

Gnomad4 OTH exome AF: 0.0263

GnomAD4 genome AF: 0.0226 AC: 3441 AN: 152330 Hom.: 75 Cov.: 32 AF XY: 0.0231 AC XY: 1718 AN XY: 74492

Gnomad4 AFR AF: 0.00416

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.0598

Gnomad4 NFE AF: 0.0323

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0296 Hom.: 25

Bravo AF: 0.0178

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	9.5
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs118002895; hg19: chr7-30668131;