rs2527878

chr7-30615873-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002047.4(GARS1):c.1032-23A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 1,613,316 control chromosomes in the GnomAD database, including 8,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (867 hom., cov: 33)
  • Exomes 𝑓: 0.097 (7956 hom.)
• Consequence: GARS1 NM_002047.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.148

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=-0.87).
• BP6: Variant 7-30615873-A-T is Benign according to our data. Variant chr7-30615873-A-T is described in ClinVar as [Benign]. Clinvar id is 258531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30615873-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GARS1	NM_002047.4	c.1032-23A>T		intron_variant		ENST00000389266.8
GARS1	NM_001316772.1	c.870-23A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GARS1	ENST00000389266.8	c.1032-23A>T		intron_variant		1	NM_002047.4	P2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15373 AN: 152088 Hom.: 865 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.0939

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.0614

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0868

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.107 AC: 26655 AN: 249006 Hom.: 1702 AF XY: 0.111 AC XY: 14967 AN XY: 135138

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0753

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.192

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.0918

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.0969 AC: 141647 AN: 1461110 Hom.: 7956 Cov.: 31 AF XY: 0.0996 AC XY: 72413 AN XY: 726854

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.0767

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.0623

Gnomad4 NFE exome AF: 0.0874

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.101 AC: 15382 AN: 152206 Hom.: 867 Cov.: 33 AF XY: 0.102 AC XY: 7585 AN XY: 74414

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0929

Gnomad4 ASJ AF: 0.0939

Gnomad4 EAS AF: 0.181

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.0614

Gnomad4 NFE AF: 0.0868

Gnomad4 OTH AF: 0.129

Alfa AF: 0.0949 Hom.: 141

Bravo AF: 0.105

Asia WGS AF: 0.214 AC: 743 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.33
Dann	Benign	0.45
La Branchor		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2527878; hg19: chr7-30655489; COSMIC: COSV66828074;