chr7-30594853-T-A

Variant names:

• chr7-30594853-T-A
• rs527307703
• ENST00000675810:c.-69T>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001316772.1(GARS1):​c.-231T>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00135 in 1,352,650 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (24 hom.)
• Consequence: GARS1 NM_001316772.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 4.85

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 7-30594853-T-A is Benign according to our data. Variant chr7-30594853-T-A is described in ClinVar as [Benign]. Clinvar id is 359998.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00133 (203/152290) while in subpopulation EAS AF= 0.0262 (135/5150). AF 95% confidence interval is 0.0226. There are 4 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 203 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_001316772.1	c.-231T>A		5_prime_UTR_variant	Exon 1 of 17		NP_001303701.1
GARS1	NM_002047.4	c.-69T>A		upstream_gene_variant		ENST00000389266.8	NP_002038.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000675810	c.-69T>A		5_prime_UTR_variant	Exon 1 of 16			ENSP00000502743.1
GARS1	ENST00000674815	c.-247T>A		5_prime_UTR_variant	Exon 1 of 17			ENSP00000502799.1
GARS1	ENST00000675051.1	c.22-3943T>A		intron_variant	Intron 1 of 16			ENSP00000502296.1
GARS1	ENST00000674643.1	n.-69T>A		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000501636.1
GARS1	ENST00000674807.1	n.-69T>A		non_coding_transcript_exon_variant	Exon 1 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.-69T>A		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.-69T>A		non_coding_transcript_exon_variant	Exon 1 of 19			ENSP00000501884.1
GARS1	ENST00000676210.1	n.-69T>A		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000502373.1
GARS1	ENST00000676403.1	n.-69T>A		non_coding_transcript_exon_variant	Exon 1 of 16			ENSP00000502681.1
GARS1	ENST00000674643.1	n.-69T>A		5_prime_UTR_variant	Exon 1 of 17			ENSP00000501636.1
GARS1	ENST00000674807.1	n.-69T>A		5_prime_UTR_variant	Exon 1 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.-69T>A		5_prime_UTR_variant	Exon 1 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.-69T>A		5_prime_UTR_variant	Exon 1 of 19			ENSP00000501884.1
GARS1	ENST00000676210.1	n.-69T>A		5_prime_UTR_variant	Exon 1 of 18			ENSP00000502373.1
GARS1	ENST00000676403.1	n.-69T>A		5_prime_UTR_variant	Exon 1 of 16			ENSP00000502681.1
GARS1	ENST00000389266.8	c.-69T>A		upstream_gene_variant		1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.-69T>A		upstream_gene_variant				ENSP00000502513.1
GARS1	ENST00000675693.1	c.-69T>A		upstream_gene_variant				ENSP00000502174.1
GARS1	ENST00000674851.1	c.-283T>A		upstream_gene_variant				ENSP00000502451.1
GARS1	ENST00000444666.6	n.-69T>A		upstream_gene_variant		3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.-69T>A		upstream_gene_variant				ENSP00000502408.1
GARS1	ENST00000674737.1	n.-69T>A		upstream_gene_variant				ENSP00000502464.1
GARS1	ENST00000675859.1	n.-69T>A		upstream_gene_variant				ENSP00000502033.1
GARS1	ENST00000676140.1	n.-69T>A		upstream_gene_variant				ENSP00000502571.1
GARS1	ENST00000676164.1	n.-69T>A		upstream_gene_variant				ENSP00000501986.1
GARS1	ENST00000676259.1	n.-69T>A		upstream_gene_variant				ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152172 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0262

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00135 AC: 1626 AN: 1200360 Hom.: 24 Cov.: 17 AF XY: 0.00131 AC XY: 784 AN XY: 600336

Gnomad4 AFR exome AF: 0.0000367

Gnomad4 AMR exome AF: 0.00770

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0362

Gnomad4 SAS exome AF: 0.0000670

Gnomad4 FIN exome AF: 0.000177

Gnomad4 NFE exome AF: 0.0000741

Gnomad4 OTH exome AF: 0.000892

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152290 Hom.: 4 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74464

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00300

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0262

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.00189

Asia WGS AF: 0.00924 AC: 32 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	-0.23
CADD	Benign	19
DANN	Benign	0.94

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: rs527307703; hg19: chr7-30634469;