rs137852648

Positions:

• chr7-30612107-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002047.4(GARS1):​c.893C>T​(p.Pro298Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1 O:1
• Conservation: PhyloP100: 7.79

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.893C>T	p.Pro298Leu	missense_variant	8/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.731C>T	p.Pro244Leu	missense_variant	8/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.893C>T	p.Pro298Leu	missense_variant	8/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.893C>T	p.Pro298Leu	missense_variant	8/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.791C>T	p.Pro264Leu	missense_variant	7/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.725C>T	p.Pro242Leu	missense_variant	9/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.692C>T	p.Pro231Leu	missense_variant	8/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.524C>T	p.Pro175Leu	missense_variant	8/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.524C>T	p.Pro175Leu	missense_variant	9/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.893C>T		non_coding_transcript_exon_variant	8/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*607C>T		non_coding_transcript_exon_variant	9/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.893C>T		non_coding_transcript_exon_variant	8/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*231C>T		non_coding_transcript_exon_variant	9/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.893C>T		non_coding_transcript_exon_variant	8/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*763C>T		non_coding_transcript_exon_variant	9/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.893C>T		non_coding_transcript_exon_variant	8/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*835C>T		non_coding_transcript_exon_variant	10/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.893C>T		non_coding_transcript_exon_variant	8/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*344C>T		non_coding_transcript_exon_variant	8/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*182C>T		non_coding_transcript_exon_variant	9/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*325C>T		non_coding_transcript_exon_variant	8/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.893C>T		non_coding_transcript_exon_variant	8/16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*607C>T		3_prime_UTR_variant	9/18			ENSP00000502408.1
GARS1	ENST00000674737.1	n.*231C>T		3_prime_UTR_variant	9/18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*763C>T		3_prime_UTR_variant	9/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*835C>T		3_prime_UTR_variant	10/19			ENSP00000501884.1
GARS1	ENST00000676164.1	n.*344C>T		3_prime_UTR_variant	8/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*182C>T		3_prime_UTR_variant	9/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*325C>T		3_prime_UTR_variant	8/17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease type 2D Pathogenic:1 Uncertain:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	GARS1-HMSN (CMT2D & dSMA-V) [Abe & Hayasaka 2009, Griffin et al 2014] -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.75	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-9.1	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.97		Loss of disorder (P = 0.0596);
MVP		0.91
MPC		1.1
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.99
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137852648; hg19: chr7-30651723;