chr7-30609652-C-T

Variant names:

• chr7-30609652-C-T
• rs2230310
• NM_002047.4:c.803C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002047.4(GARS1):​c.803C>T​(p.Thr268Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00393 in 1,613,140 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T268T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (19 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 6.04
• Publications: 15 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• neuronopathy, distal hereditary motor, type 5A

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

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_002047.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011372536).
• BP6: Variant 7-30609652-C-T is Benign according to our data. Variant chr7-30609652-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 188100.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 = 0.00352 (536/152290) while in subpopulation NFE AF = 0.00546 (371/68004). AF 95% confidence interval is 0.005. There are 2 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 536 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	NM_002047.4	MANE Select	c.803C>T	p.Thr268Ile	missense	Exon 7 of 17	NP_002038.2	P41250-1
	GARS1	NM_001316772.1		c.641C>T	p.Thr214Ile	missense	Exon 7 of 17	NP_001303701.1	P41250-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000389266.8	TSL:1 MANE Select	c.803C>T	p.Thr268Ile	missense	Exon 7 of 17	ENSP00000373918.3	P41250-1
	GARS1	ENST00000675651.1		c.803C>T	p.Thr268Ile	missense	Exon 7 of 17	ENSP00000502513.1	A0A6Q8PGZ8
	GARS1	ENST00000675810.1		c.701C>T	p.Thr234Ile	missense	Exon 6 of 16	ENSP00000502743.1	A0A6Q8PHH9

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 536 AN: 152172 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00545

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00344 AC: 857 AN: 249452 AF XY: 0.00330

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00745

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00492

Gnomad NFE exome AF: 0.00503

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00397 AC: 5805 AN: 1460850 Hom.: 19 Cov.: 30 AF XY: 0.00403 AC XY: 2929 AN XY: 726828

African (AFR) AF: 0.000628 AC: 21 AN: 33446

American (AMR) AF: 0.00186 AC: 83 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00716 AC: 187 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86230

European-Finnish (FIN) AF: 0.00436 AC: 233 AN: 53398

Middle Eastern (MID) AF: 0.00781 AC: 45 AN: 5764

European-Non Finnish (NFE) AF: 0.00441 AC: 4903 AN: 1111198

Other (OTH) AF: 0.00461 AC: 278 AN: 60356

GnomAD4 genome AF: 0.00352 AC: 536 AN: 152290 Hom.: 2 Cov.: 33 AF XY: 0.00310 AC XY: 231 AN XY: 74474

African (AFR) AF: 0.000770 AC: 32 AN: 41566

American (AMR) AF: 0.00366 AC: 56 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00546 AC: 371 AN: 68004

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00354 Hom.: 10

Bravo AF: 0.00342

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00109 AC: 4

ESP6500EA AF: 0.00651 AC: 53

ExAC AF: 0.00317 AC: 383

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00573

EpiControl AF: 0.00533

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (9)
-	-	3	not specified (3)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Charcot-Marie-Tooth disease type 2D (1)
-	-	1	Distal spinal muscular atrophy (1)
-	-	1	GARS1-related disorder (1)
-	-	1	Neuronopathy, distal hereditary motor, type 5A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.049	D
PhyloP100		6.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.66	P
Vest4		0.48
MVP		0.66
MPC		0.99
ClinPred		0.11	T
GERP RS		4.9
Varity_R		0.48
gMVP		0.65
Mutation Taster		=23/77	disease causing

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: rs2230310; hg19: chr7-30649268;