7-30612214-A-T

Variant names:

• chr7-30612214-A-T
• rs1554338260
• NM_002047.4:c.1000A>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_002047.4(GARS1):​c.1000A>T​(p.Ile334Phe) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:3 O:1
• Conservation: PhyloP100: 9.22

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 7-30612214-A-T is Pathogenic according to our data. Variant chr7-30612214-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 476747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30612214-A-T is described in Lovd as [Pathogenic]. Variant chr7-30612214-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1000A>T	p.Ile334Phe	missense_variant	Exon 8 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.838A>T	p.Ile280Phe	missense_variant	Exon 8 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1000A>T	p.Ile334Phe	missense_variant	Exon 8 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1000A>T	p.Ile334Phe	missense_variant	Exon 8 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.898A>T	p.Ile300Phe	missense_variant	Exon 7 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.832A>T	p.Ile278Phe	missense_variant	Exon 9 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.799A>T	p.Ile267Phe	missense_variant	Exon 8 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.631A>T	p.Ile211Phe	missense_variant	Exon 8 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.631A>T	p.Ile211Phe	missense_variant	Exon 9 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1000A>T		non_coding_transcript_exon_variant	Exon 8 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*714A>T		non_coding_transcript_exon_variant	Exon 9 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.1000A>T		non_coding_transcript_exon_variant	Exon 8 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*338A>T		non_coding_transcript_exon_variant	Exon 9 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1000A>T		non_coding_transcript_exon_variant	Exon 8 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*870A>T		non_coding_transcript_exon_variant	Exon 9 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1000A>T		non_coding_transcript_exon_variant	Exon 8 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*942A>T		non_coding_transcript_exon_variant	Exon 10 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.1000A>T		non_coding_transcript_exon_variant	Exon 8 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*451A>T		non_coding_transcript_exon_variant	Exon 8 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*289A>T		non_coding_transcript_exon_variant	Exon 9 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*432A>T		non_coding_transcript_exon_variant	Exon 8 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1000A>T		non_coding_transcript_exon_variant	Exon 8 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*714A>T		3_prime_UTR_variant	Exon 9 of 18			ENSP00000502408.1
GARS1	ENST00000674737.1	n.*338A>T		3_prime_UTR_variant	Exon 9 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*870A>T		3_prime_UTR_variant	Exon 9 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*942A>T		3_prime_UTR_variant	Exon 10 of 19			ENSP00000501884.1
GARS1	ENST00000676164.1	n.*451A>T		3_prime_UTR_variant	Exon 8 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*289A>T		3_prime_UTR_variant	Exon 9 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*432A>T		3_prime_UTR_variant	Exon 8 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 15, 2019

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality (0/280908 chr). Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease in affected individuals from a single family. -

May 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies show large reduction in aminoacylation activity relative to wildtype (Griffin et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25476837, 17101916, 26503042, 26138142, 25168514, 32181591, 24604904, 35332613, 31628756) -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Dec 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 334 of the GARS protein (p.Ile334Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with GARS-related conditions (PMID: 17101916, 24604904, 25476837; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as I120F and I280F. ClinVar contains an entry for this variant (Variation ID: 476747). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GARS protein function. Experimental studies have shown that this missense change affects GARS function (PMID: 25168514). For these reasons, this variant has been classified as Pathogenic. -

Neuronopathy, distal hereditary motor, type 5A Pathogenic:1

Jun 22, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Distal spinal muscular atrophy Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neuronopathy, distal hereditary motor, type 5 Uncertain:1

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

GARS1-HMSN (CMT2D) [James et al 2006, Griffin et al 2014] -

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	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.59	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.95		Loss of catalytic residue at P336 (P = 0.0354);
MVP		0.88
MPC		1.4
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.86

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: rs1554338260; hg19: chr7-30651830;