rs530891983

Positions:

• chr7-30633799-A-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_002047.4(GARS1):​c.2159A>C​(p.Glu720Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,608,106 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B: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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000618 (9/1456182) while in subpopulation AMR AF= 0.000202 (9/44502). AF 95% confidence interval is 0.000105. There are 0 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 42. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.2159A>C	p.Glu720Ala	missense_variant	17/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1997A>C	p.Glu666Ala	missense_variant	17/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.2159A>C	p.Glu720Ala	missense_variant	17/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.2177A>C	p.Glu726Ala	missense_variant	17/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.2057A>C	p.Glu686Ala	missense_variant	16/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1991A>C	p.Glu664Ala	missense_variant	18/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1958A>C	p.Glu653Ala	missense_variant	17/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1790A>C	p.Glu597Ala	missense_variant	17/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1790A>C	p.Glu597Ala	missense_variant	18/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*580A>C		non_coding_transcript_exon_variant	18/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1873A>C		non_coding_transcript_exon_variant	18/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*1964A>C		non_coding_transcript_exon_variant	17/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1497A>C		non_coding_transcript_exon_variant	18/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*432A>C		non_coding_transcript_exon_variant	16/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*2029A>C		non_coding_transcript_exon_variant	18/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*338A>C		non_coding_transcript_exon_variant	15/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*2101A>C		non_coding_transcript_exon_variant	19/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*1104A>C		non_coding_transcript_exon_variant	17/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1610A>C		non_coding_transcript_exon_variant	17/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1448A>C		non_coding_transcript_exon_variant	18/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1591A>C		non_coding_transcript_exon_variant	17/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.*244A>C		non_coding_transcript_exon_variant	16/16			ENSP00000502681.1
GARS1	ENST00000444666.6	n.*580A>C		3_prime_UTR_variant	18/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1873A>C		3_prime_UTR_variant	18/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*1964A>C		3_prime_UTR_variant	17/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1497A>C		3_prime_UTR_variant	18/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*432A>C		3_prime_UTR_variant	16/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*2029A>C		3_prime_UTR_variant	18/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*338A>C		3_prime_UTR_variant	15/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*2101A>C		3_prime_UTR_variant	19/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*1104A>C		3_prime_UTR_variant	17/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1610A>C		3_prime_UTR_variant	17/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1448A>C		3_prime_UTR_variant	18/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1591A>C		3_prime_UTR_variant	17/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.*244A>C		3_prime_UTR_variant	16/16			ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151800 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 249546 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1456182 Hom.: 0 Cov.: 42 AF XY: 0.00000414 AC XY: 3 AN XY: 724468

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000202

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151924 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74250

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

The c.2159A>C (p.E720A) alteration is located in exon 17 (coding exon 17) of the GARS gene. This alteration results from a A to C substitution at nucleotide position 2159, causing the glutamic acid (E) at amino acid position 720 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 18, 2017

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 19, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Charcot-Marie-Tooth disease type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.010
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.47	T
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.49
Sift	Benign	0.81	T
Sift4G	Benign	0.89	T
Polyphen		0.010	B
Vest4		0.69
MutPred		0.38		Gain of catalytic residue at D718 (P = 0.2132);
MVP		0.84
MPC		0.56
ClinPred		0.52	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.75

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: rs530891983; hg19: chr7-30673415;