chr7-30594745-T-C

Variant names:

• chr7-30594745-T-C
• rs78980639
• ENST00000675051.1:c.22-4051T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001316772.1(GARS1):​c.-339T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00555 in 603,942 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (13 hom.)
• Consequence: GARS1 NM_001316772.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.177
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 7-30594745-T-C is Benign according to our data. Variant chr7-30594745-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 359996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0044 (669/152208) while in subpopulation EAS AF = 0.0124 (64/5174). AF 95% confidence interval is 0.00994. There are 8 homozygotes in GnomAd4. There are 343 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 669 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.-339T>C		5_prime_UTR	Exon 1 of 17	NP_001303701.1	P41250-2
	GARS1	NM_002047.4	MANE Select	c.-177T>C		upstream_gene	N/A	NP_002038.2	P41250-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000675051.1		c.22-4051T>C		intron	N/A	ENSP00000502296.1	A0A6Q8PGI6
	GARS1-DT	ENST00000578994.6	TSL:4	n.65A>G		non_coding_transcript_exon	Exon 1 of 5
	GARS1-DT	ENST00000579174.5	TSL:3	n.64A>G		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes AF: 0.00441 AC: 670 AN: 152090 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00594 AC: 2685 AN: 451734 Hom.: 13 Cov.: 5 AF XY: 0.00568 AC XY: 1355 AN XY: 238612

African (AFR) AF: 0.00101 AC: 11 AN: 10888

American (AMR) AF: 0.00155 AC: 29 AN: 18724

Ashkenazi Jewish (ASJ) AF: 0.00418 AC: 56 AN: 13384

East Asian (EAS) AF: 0.0185 AC: 544 AN: 29394

South Asian (SAS) AF: 0.00212 AC: 97 AN: 45684

European-Finnish (FIN) AF: 0.0116 AC: 345 AN: 29644

Middle Eastern (MID) AF: 0.000992 AC: 2 AN: 2016

European-Non Finnish (NFE) AF: 0.00540 AC: 1490 AN: 275970

Other (OTH) AF: 0.00426 AC: 111 AN: 26030

GnomAD4 genome AF: 0.00440 AC: 669 AN: 152208 Hom.: 8 Cov.: 32 AF XY: 0.00461 AC XY: 343 AN XY: 74426

African (AFR) AF: 0.00106 AC: 44 AN: 41512

American (AMR) AF: 0.00235 AC: 36 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.0124 AC: 64 AN: 5174

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00532 AC: 362 AN: 67996

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00377 Hom.: 0

Bravo AF: 0.00348

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	12
DANN	Benign	0.70
PhyloP100		-0.18
PromoterAI		0.15	Neutral
Mutation Taster		=300/0	polymorphism

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: rs78980639; hg19: chr7-30634361;