7-30594858-C-T

Position:

• chr7-30594858-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001316772.1(GARS1):​c.-226C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000721 in 1,387,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: GARS1 NM_001316772.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: -0.491

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_001316772.1	c.-226C>T		5_prime_UTR_premature_start_codon_gain_variant	1/17		NP_001303701.1
GARS1	NM_001316772.1	c.-226C>T		5_prime_UTR_variant	1/17		NP_001303701.1
GARS1	NM_002047.4	c.-64C>T		upstream_gene_variant		ENST00000389266.8	NP_002038.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000675810	c.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	1/16			ENSP00000502743.1
GARS1	ENST00000674815	c.-242C>T		5_prime_UTR_premature_start_codon_gain_variant	1/17			ENSP00000502799.1
GARS1	ENST00000675810	c.-64C>T		5_prime_UTR_variant	1/16			ENSP00000502743.1
GARS1	ENST00000674815	c.-242C>T		5_prime_UTR_variant	1/17			ENSP00000502799.1
GARS1	ENST00000675051.1	c.22-3938C>T		intron_variant				ENSP00000502296.1
GARS1	ENST00000674643.1	n.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	1/17			ENSP00000501636.1
GARS1	ENST00000674807.1	n.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	1/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	1/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	1/19			ENSP00000501884.1
GARS1	ENST00000676210.1	n.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	1/18			ENSP00000502373.1
GARS1	ENST00000676403.1	n.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	1/16			ENSP00000502681.1
GARS1	ENST00000674643.1	n.-64C>T		non_coding_transcript_exon_variant	1/17			ENSP00000501636.1
GARS1	ENST00000674807.1	n.-64C>T		non_coding_transcript_exon_variant	1/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.-64C>T		non_coding_transcript_exon_variant	1/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.-64C>T		non_coding_transcript_exon_variant	1/19			ENSP00000501884.1
GARS1	ENST00000676210.1	n.-64C>T		non_coding_transcript_exon_variant	1/18			ENSP00000502373.1
GARS1	ENST00000676403.1	n.-64C>T		non_coding_transcript_exon_variant	1/16			ENSP00000502681.1
GARS1	ENST00000674643.1	n.-64C>T		5_prime_UTR_variant	1/17			ENSP00000501636.1
GARS1	ENST00000674807.1	n.-64C>T		5_prime_UTR_variant	1/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.-64C>T		5_prime_UTR_variant	1/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.-64C>T		5_prime_UTR_variant	1/19			ENSP00000501884.1
GARS1	ENST00000676210.1	n.-64C>T		5_prime_UTR_variant	1/18			ENSP00000502373.1
GARS1	ENST00000676403.1	n.-64C>T		5_prime_UTR_variant	1/16			ENSP00000502681.1
GARS1	ENST00000389266.8	c.-64C>T		upstream_gene_variant		1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.-64C>T		upstream_gene_variant				ENSP00000502513.1
GARS1	ENST00000675693.1	c.-64C>T		upstream_gene_variant				ENSP00000502174.1
GARS1	ENST00000674851.1	c.-278C>T		upstream_gene_variant				ENSP00000502451.1
GARS1	ENST00000444666.6	n.-64C>T		upstream_gene_variant		3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.-64C>T		upstream_gene_variant				ENSP00000502408.1
GARS1	ENST00000674737.1	n.-64C>T		upstream_gene_variant				ENSP00000502464.1
GARS1	ENST00000675859.1	n.-64C>T		upstream_gene_variant				ENSP00000502033.1
GARS1	ENST00000676140.1	n.-64C>T		upstream_gene_variant				ENSP00000502571.1
GARS1	ENST00000676164.1	n.-64C>T		upstream_gene_variant				ENSP00000501986.1
GARS1	ENST00000676259.1	n.-64C>T		upstream_gene_variant				ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000648 AC: 8 AN: 1234892 Hom.: 0 Cov.: 18 AF XY: 0.00000487 AC XY: 3 AN XY: 616026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000844

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Distal spinal muscular atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.9
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs932663016; hg19: chr7-30634474;