rs1554337983

Variant names:

• chr7-30609667-C-T
• rs1554337983
• NM_002047.4:c.818C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002047.4(GARS1):​c.818C>T​(p.Ser273Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,966 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.818C>T	p.Ser273Phe	missense_variant	Exon 7 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.656C>T	p.Ser219Phe	missense_variant	Exon 7 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.818C>T	p.Ser273Phe	missense_variant	Exon 7 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.818C>T	p.Ser273Phe	missense_variant	Exon 7 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.716C>T	p.Ser239Phe	missense_variant	Exon 6 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.650C>T	p.Ser217Phe	missense_variant	Exon 8 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.617C>T	p.Ser206Phe	missense_variant	Exon 7 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.449C>T	p.Ser150Phe	missense_variant	Exon 7 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.449C>T	p.Ser150Phe	missense_variant	Exon 8 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.818C>T		non_coding_transcript_exon_variant	Exon 7 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*532C>T		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.818C>T		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*156C>T		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.818C>T		non_coding_transcript_exon_variant	Exon 7 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*688C>T		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.818C>T		non_coding_transcript_exon_variant	Exon 7 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*760C>T		non_coding_transcript_exon_variant	Exon 9 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.818C>T		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*269C>T		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*107C>T		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*250C>T		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.818C>T		non_coding_transcript_exon_variant	Exon 7 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*532C>T		3_prime_UTR_variant	Exon 8 of 18			ENSP00000502408.1
GARS1	ENST00000674737.1	n.*156C>T		3_prime_UTR_variant	Exon 8 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*688C>T		3_prime_UTR_variant	Exon 8 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*760C>T		3_prime_UTR_variant	Exon 9 of 19			ENSP00000501884.1
GARS1	ENST00000676164.1	n.*269C>T		3_prime_UTR_variant	Exon 7 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*107C>T		3_prime_UTR_variant	Exon 8 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*250C>T		3_prime_UTR_variant	Exon 7 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460966 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726852

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Apr 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 543165). This variant has not been reported in the literature in individuals affected with GARS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 273 of the GARS protein (p.Ser273Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.30	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.51
MutPred		0.64		Loss of disorder (P = 0.0088);
MVP		0.62
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.62
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554337983; hg19: chr7-30649283;