rs751505742

Positions:

• chr7-30601081-T-A
• chr7-30601081-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002047.4(GARS1):​c.450T>A​(p.Phe150Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.200

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.450T>A	p.Phe150Leu	missense_variant	4/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.288T>A	p.Phe96Leu	missense_variant	4/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.450T>A	p.Phe150Leu	missense_variant	4/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.450T>A	p.Phe150Leu	missense_variant	4/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.348T>A	p.Phe116Leu	missense_variant	3/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.282T>A	p.Phe94Leu	missense_variant	5/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.249T>A	p.Phe83Leu	missense_variant	4/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.81T>A	p.Phe27Leu	missense_variant	4/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.81T>A	p.Phe27Leu	missense_variant	5/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.450T>A		non_coding_transcript_exon_variant	4/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*164T>A		non_coding_transcript_exon_variant	5/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.450T>A		non_coding_transcript_exon_variant	4/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.450T>A		non_coding_transcript_exon_variant	4/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.450T>A		non_coding_transcript_exon_variant	4/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*320T>A		non_coding_transcript_exon_variant	5/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.450T>A		non_coding_transcript_exon_variant	4/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*320T>A		non_coding_transcript_exon_variant	5/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.450T>A		non_coding_transcript_exon_variant	4/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.450T>A		non_coding_transcript_exon_variant	4/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.450T>A		non_coding_transcript_exon_variant	4/18			ENSP00000502373.1
GARS1	ENST00000676403.1	n.450T>A		non_coding_transcript_exon_variant	4/16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*164T>A		3_prime_UTR_variant	5/18			ENSP00000502408.1
GARS1	ENST00000675529.1	n.*320T>A		3_prime_UTR_variant	5/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*320T>A		3_prime_UTR_variant	5/19			ENSP00000501884.1
GARS1	ENST00000676259.1	n.428-48T>A		intron_variant				ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2018

This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 150 of the GARS protein (p.Phe150Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant has not been reported in the literature in individuals with GARS-related disease. 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.89	T
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.025	D
Sift4G	Benign	0.14	T
Polyphen		0.0070	B
Vest4		0.48
MutPred		0.74		Loss of catalytic residue at F150 (P = 0.0622);
MVP		0.50
MPC		0.41
ClinPred		0.91	D
GERP RS		0.043
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs751505742; hg19: chr7-30640697;