7-30621453-C-T

Variant names:

• chr7-30621453-C-T
• NM_002047.4:c.1420C>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_002047.4(GARS1):​c.1420C>T​(p.Arg474*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GARS1 NM_002047.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.389

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1420C>T	p.Arg474*	stop_gained	Exon 11 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1258C>T	p.Arg420*	stop_gained	Exon 11 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1420C>T	p.Arg474*	stop_gained	Exon 11 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1420C>T	p.Arg474*	stop_gained	Exon 11 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1318C>T	p.Arg440*	stop_gained	Exon 10 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1252C>T	p.Arg418*	stop_gained	Exon 12 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1219C>T	p.Arg407*	stop_gained	Exon 11 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1051C>T	p.Arg351*	stop_gained	Exon 11 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1051C>T	p.Arg351*	stop_gained	Exon 12 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1420C>T		non_coding_transcript_exon_variant	Exon 11 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1134C>T		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*520C>T		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*758C>T		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1420C>T		non_coding_transcript_exon_variant	Exon 11 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1290C>T		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1420C>T		non_coding_transcript_exon_variant	Exon 11 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1362C>T		non_coding_transcript_exon_variant	Exon 13 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*365C>T		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*871C>T		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*709C>T		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*852C>T		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1420C>T		non_coding_transcript_exon_variant	Exon 11 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*1134C>T		3_prime_UTR_variant	Exon 12 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*520C>T		3_prime_UTR_variant	Exon 12 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*758C>T		3_prime_UTR_variant	Exon 12 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*1290C>T		3_prime_UTR_variant	Exon 12 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1362C>T		3_prime_UTR_variant	Exon 13 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*365C>T		3_prime_UTR_variant	Exon 11 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*871C>T		3_prime_UTR_variant	Exon 11 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*709C>T		3_prime_UTR_variant	Exon 12 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*852C>T		3_prime_UTR_variant	Exon 11 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg474*) in the GARS gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in GARS cause disease. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GARS-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.23	N
Vest4		0.98
GERP RS		-0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-30661069;