7-30594642-G-A

Variant names:

• chr7-30594642-G-A
• rs73294431
• ENST00000675051.1:c.22-4154G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000675051.1(GARS1):​c.22-4154G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 530,942 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: GARS1 ENST00000675051.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.0880

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-DT (HGNC:48951): (GARS1 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-30594642-G-A is Benign according to our data. Variant chr7-30594642-G-A is described in ClinVar as [Benign]. Clinvar id is 910408.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00336 (511/152298) while in subpopulation AFR AF= 0.0118 (490/41576). AF 95% confidence interval is 0.0109. There are 3 homozygotes in gnomad4. There are 233 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 511 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.-280G>A		upstream_gene_variant		ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.-442G>A		upstream_gene_variant			NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000675051.1	c.22-4154G>A		intron_variant	Intron 1 of 16			ENSP00000502296.1
GARS1	ENST00000389266.8	c.-280G>A		upstream_gene_variant		1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.-280G>A		upstream_gene_variant				ENSP00000502513.1
GARS1	ENST00000675810.1	c.-280G>A		upstream_gene_variant				ENSP00000502743.1
GARS1	ENST00000675693.1	c.-280G>A		upstream_gene_variant				ENSP00000502174.1
GARS1	ENST00000674815.1	c.-458G>A		upstream_gene_variant				ENSP00000502799.1
GARS1	ENST00000674616.1	n.-280G>A		upstream_gene_variant				ENSP00000502408.1
GARS1	ENST00000674643.1	n.-280G>A		upstream_gene_variant				ENSP00000501636.1
GARS1	ENST00000674737.1	n.-280G>A		upstream_gene_variant				ENSP00000502464.1
GARS1	ENST00000674807.1	n.-280G>A		upstream_gene_variant				ENSP00000502814.1
GARS1	ENST00000675529.1	n.-280G>A		upstream_gene_variant				ENSP00000501655.1
GARS1	ENST00000675859.1	n.-280G>A		upstream_gene_variant				ENSP00000502033.1
GARS1	ENST00000676088.1	n.-280G>A		upstream_gene_variant				ENSP00000501884.1
GARS1	ENST00000676140.1	n.-280G>A		upstream_gene_variant				ENSP00000502571.1
GARS1	ENST00000676164.1	n.-280G>A		upstream_gene_variant				ENSP00000501986.1
GARS1	ENST00000676210.1	n.-280G>A		upstream_gene_variant				ENSP00000502373.1
GARS1	ENST00000676259.1	n.-280G>A		upstream_gene_variant				ENSP00000501980.1
GARS1	ENST00000676403.1	n.-280G>A		upstream_gene_variant				ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 511 AN: 152180 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000959

GnomAD4 exome AF: 0.000349 AC: 132 AN: 378644 Hom.: 1 Cov.: 0 AF XY: 0.000246 AC XY: 49 AN XY: 198824

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.000801

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000435

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00336 AC: 511 AN: 152298 Hom.: 3 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74464

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00408

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Distal spinal muscular atrophy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 2D Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Neuronopathy, distal hereditary motor, type 5A Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.2
DANN	Benign	0.85

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs73294431; hg19: chr7-30634258;