chr7-30617256-A-T

Variant names:

• chr7-30617256-A-T
• rs1554338834
• NM_002047.4:c.1337A>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.1337A>T​(p.Asp446Val) 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 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: 9.29

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 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, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1337A>T	p.Asp446Val	missense_variant	Exon 10 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1175A>T	p.Asp392Val	missense_variant	Exon 10 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1337A>T	p.Asp446Val	missense_variant	Exon 10 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1337A>T	p.Asp446Val	missense_variant	Exon 10 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1235A>T	p.Asp412Val	missense_variant	Exon 9 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1169A>T	p.Asp390Val	missense_variant	Exon 11 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1136A>T	p.Asp379Val	missense_variant	Exon 10 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.968A>T	p.Asp323Val	missense_variant	Exon 10 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.968A>T	p.Asp323Val	missense_variant	Exon 11 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1337A>T		non_coding_transcript_exon_variant	Exon 10 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1051A>T		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*437A>T		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*675A>T		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1337A>T		non_coding_transcript_exon_variant	Exon 10 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1207A>T		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1337A>T		non_coding_transcript_exon_variant	Exon 10 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1279A>T		non_coding_transcript_exon_variant	Exon 12 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*282A>T		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*788A>T		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*626A>T		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*769A>T		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1337A>T		non_coding_transcript_exon_variant	Exon 10 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*1051A>T		3_prime_UTR_variant	Exon 11 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*437A>T		3_prime_UTR_variant	Exon 11 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*675A>T		3_prime_UTR_variant	Exon 11 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*1207A>T		3_prime_UTR_variant	Exon 11 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1279A>T		3_prime_UTR_variant	Exon 12 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*282A>T		3_prime_UTR_variant	Exon 10 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*788A>T		3_prime_UTR_variant	Exon 10 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*626A>T		3_prime_UTR_variant	Exon 11 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*769A>T		3_prime_UTR_variant	Exon 10 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Nov 23, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid with valine at codon 446 of the GARS protein (p.Asp446Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GARS-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.91	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.89		Loss of helix (P = 0.0376);
MVP		0.95
MPC		1.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.93

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: rs1554338834; hg19: chr7-30656872;