rs73294431

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 511 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000675051.1. 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_002047.4	MANE Select	c.-280G>A		upstream_gene	N/A	NP_002038.2	P41250-1
	GARS1	NM_001316772.1		c.-442G>A		upstream_gene	N/A	NP_001303701.1	P41250-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000675051.1		c.22-4154G>A		intron	N/A	ENSP00000502296.1	A0A6Q8PGI6
	GARS1-DT	ENST00000785598.1		n.91C>T		non_coding_transcript_exon	Exon 1 of 1
	GARS1-DT	ENST00000426529.6	TSL:5	n.33+69C>T		intron	N/A

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

African (AFR) AF: 0.0105 AC: 85 AN: 8092

American (AMR) AF: 0.000801 AC: 11 AN: 13726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11656

East Asian (EAS) AF: 0.00 AC: 0 AN: 24268

South Asian (SAS) AF: 0.00 AC: 0 AN: 40320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26304

Middle Eastern (MID) AF: 0.000588 AC: 1 AN: 1702

European-Non Finnish (NFE) AF: 0.00000435 AC: 1 AN: 230140

Other (OTH) AF: 0.00152 AC: 34 AN: 22436

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

African (AFR) AF: 0.0118 AC: 490 AN: 41576

American (AMR) AF: 0.000915 AC: 14 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00408

Asia WGS AF: 0.000577 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

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	-0.79
CADD	Benign	3.2
DANN	Benign	0.85
PhyloP100		-0.088
PromoterAI		0.010	Neutral

Splicing

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

Other links and lift over

dbSNP: rs73294431; hg19: chr7-30634258;