chr7-30594863-C-T

Variant names:

• chr7-30594863-C-T
• rs886062271
• ENST00000675810.1:c.-59C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001316772.1(GARS1):​c.-221C>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 0.000135 in 1,406,884 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (2 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: -0.285
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000722 (11/152284) while in subpopulation EAS AF = 0.00193 (10/5168). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001316772.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	NM_001316772.1		c.-221C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001303701.1	P41250-2
	GARS1	NM_001316772.1		c.-221C>T		5_prime_UTR	Exon 1 of 17	NP_001303701.1	P41250-2
	GARS1	NM_002047.4	MANE Select	c.-59C>T		upstream_gene	N/A	NP_002038.2	P41250-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000675810.1		c.-59C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000502743.1	A0A6Q8PHH9
	GARS1	ENST00000674815.1		c.-237C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000502799.1	A0A6Q8PGW4
	GARS1	ENST00000675810.1		c.-59C>T		5_prime_UTR	Exon 1 of 16	ENSP00000502743.1	A0A6Q8PHH9

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 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: 0.00193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000143 AC: 179 AN: 1254600 Hom.: 2 Cov.: 19 AF XY: 0.000146 AC XY: 91 AN XY: 624842

African (AFR) AF: 0.00 AC: 0 AN: 28464

American (AMR) AF: 0.00 AC: 0 AN: 34716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24160

East Asian (EAS) AF: 0.00507 AC: 176 AN: 34682

South Asian (SAS) AF: 0.00 AC: 0 AN: 76080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3846

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 964950

Other (OTH) AF: 0.0000375 AC: 2 AN: 53384

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease type 2D (1)
-	1	-	Distal spinal muscular atrophy (1)
-	1	-	Neuronopathy, distal hereditary motor, type 5A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.7
DANN	Benign	0.96
PhyloP100		-0.28
PromoterAI		-0.013	Neutral
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

Other links and lift over

dbSNP: rs886062271; hg19: chr7-30634479;