NM_002047.4:c.1700-45T>C

Variant names:

• chr7-30628515-T-C
• rs118002895
• NM_002047.4:c.1700-45T>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_002047.4(GARS1):​c.1700-45T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,325,674 control chromosomes in the GnomAD database, including 664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (75 hom., cov: 32)
  • Exomes 𝑓: 0.029 (589 hom.)
• Consequence: GARS1 NM_002047.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.626
• 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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 2D

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, type 5A

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Laboratory for Molecular Medicine
• spinal muscular atrophy, infantile, James type

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 7-30628515-T-C is Benign according to our data. Variant chr7-30628515-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0226 (3441/152330) while in subpopulation NFE AF = 0.0323 (2196/68028). AF 95% confidence interval is 0.0312. There are 75 homozygotes in GnomAd4. There are 1718 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3441 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002047.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	NM_002047.4	MANE Select	c.1700-45T>C		intron	N/A	NP_002038.2
	GARS1	NM_001316772.1		c.1538-45T>C		intron	N/A	NP_001303701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000389266.8	TSL:1 MANE Select	c.1700-45T>C		intron	N/A	ENSP00000373918.3
	GARS1	ENST00000675651.1		c.1700-45T>C		intron	N/A	ENSP00000502513.1
	GARS1	ENST00000675810.1		c.1598-45T>C		intron	N/A	ENSP00000502743.1

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3443 AN: 152212 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0598

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0244 AC: 6089 AN: 249392 AF XY: 0.0250

Gnomad AFR exome AF: 0.00459

Gnomad AMR exome AF: 0.00964

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0551

Gnomad NFE exome AF: 0.0317

Gnomad OTH exome AF: 0.0213

GnomAD4 exome AF: 0.0289 AC: 33960 AN: 1173344 Hom.: 589 Cov.: 15 AF XY: 0.0290 AC XY: 17339 AN XY: 598030

African (AFR) AF: 0.00405 AC: 112 AN: 27634

American (AMR) AF: 0.00957 AC: 421 AN: 43996

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 642 AN: 23942

East Asian (EAS) AF: 0.0000530 AC: 2 AN: 37712

South Asian (SAS) AF: 0.0186 AC: 1502 AN: 80542

European-Finnish (FIN) AF: 0.0530 AC: 2789 AN: 52612

Middle Eastern (MID) AF: 0.0200 AC: 104 AN: 5198

European-Non Finnish (NFE) AF: 0.0318 AC: 27067 AN: 851458

Other (OTH) AF: 0.0263 AC: 1321 AN: 50250

GnomAD4 genome AF: 0.0226 AC: 3441 AN: 152330 Hom.: 75 Cov.: 32 AF XY: 0.0231 AC XY: 1718 AN XY: 74492

African (AFR) AF: 0.00416 AC: 173 AN: 41586

American (AMR) AF: 0.0120 AC: 183 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 83 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4826

European-Finnish (FIN) AF: 0.0598 AC: 635 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0323 AC: 2196 AN: 68028

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.0299 Hom.: 97

Bravo AF: 0.0178

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.5
DANN	Benign	0.81
PhyloP100		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs118002895; hg19: chr7-30668131;