chr7-30622417-A-T

Position:

• chr7-30622417-A-T

Variant summary

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

The NM_002047.4(GARS1):​c.1568A>T​(p.Asp523Val) variant causes a missense change involving the alteration of a 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• 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]

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.1568A>T	p.Asp523Val	missense_variant	12/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1406A>T	p.Asp469Val	missense_variant	12/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1568A>T	p.Asp523Val	missense_variant	12/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1568A>T	p.Asp523Val	missense_variant	12/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1466A>T	p.Asp489Val	missense_variant	11/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1400A>T	p.Asp467Val	missense_variant	13/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1367A>T	p.Asp456Val	missense_variant	12/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1199A>T	p.Asp400Val	missense_variant	12/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1199A>T	p.Asp400Val	missense_variant	13/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1568A>T		non_coding_transcript_exon_variant	12/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1282A>T		non_coding_transcript_exon_variant	13/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*668A>T		non_coding_transcript_exon_variant	13/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*906A>T		non_coding_transcript_exon_variant	13/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1568A>T		non_coding_transcript_exon_variant	12/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1438A>T		non_coding_transcript_exon_variant	13/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1568A>T		non_coding_transcript_exon_variant	12/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1510A>T		non_coding_transcript_exon_variant	14/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*513A>T		non_coding_transcript_exon_variant	12/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1019A>T		non_coding_transcript_exon_variant	12/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*857A>T		non_coding_transcript_exon_variant	13/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1000A>T		non_coding_transcript_exon_variant	12/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1568A>T		non_coding_transcript_exon_variant	12/16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*1282A>T		3_prime_UTR_variant	13/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*668A>T		3_prime_UTR_variant	13/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*906A>T		3_prime_UTR_variant	13/18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*1438A>T		3_prime_UTR_variant	13/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1510A>T		3_prime_UTR_variant	14/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*513A>T		3_prime_UTR_variant	12/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1019A>T		3_prime_UTR_variant	12/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*857A>T		3_prime_UTR_variant	13/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1000A>T		3_prime_UTR_variant	12/17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249560 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727222

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

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

Nov 10, 2022

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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt GARS protein function. ClinVar contains an entry for this variant (Variation ID: 188352). This variant has not been reported in the literature in individuals affected with GARS-related conditions. This variant is present in population databases (rs779225125, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 523 of the GARS protein (p.Asp523Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.26	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.026	D
Polyphen		0.28	B
Vest4		0.46
MutPred		0.59		Gain of helix (P = 0.0225);
MVP		0.71
MPC		0.65
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.59
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs779225125; hg19: chr7-30662033; COSMIC: COSV66828121; COSMIC: COSV66828121;