rs764238525

Variant names:

• chr7-30628575-C-T
• rs764238525
• NM_002047.4:c.1715C>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PP3_Strong BS1_Supporting BS2

The NM_002047.4(GARS1):​c.1715C>T​(p.Pro572Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,610,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P572P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 7.88

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_benign. Variant got -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000394 (6/152132) while in subpopulation NFE AF= 0.0000735 (5/68030). AF 95% confidence interval is 0.0000285. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1715C>T	p.Pro572Leu	missense_variant	Exon 14 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1553C>T	p.Pro518Leu	missense_variant	Exon 14 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1715C>T	p.Pro572Leu	missense_variant	Exon 14 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1715C>T	p.Pro572Leu	missense_variant	Exon 14 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1613C>T	p.Pro538Leu	missense_variant	Exon 13 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1547C>T	p.Pro516Leu	missense_variant	Exon 15 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1514C>T	p.Pro505Leu	missense_variant	Exon 14 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1346C>T	p.Pro449Leu	missense_variant	Exon 14 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1346C>T	p.Pro449Leu	missense_variant	Exon 15 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*136C>T		non_coding_transcript_exon_variant	Exon 15 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1429C>T		non_coding_transcript_exon_variant	Exon 15 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*815C>T		non_coding_transcript_exon_variant	Exon 15 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1053C>T		non_coding_transcript_exon_variant	Exon 15 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1629C>T		non_coding_transcript_exon_variant	Exon 13 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1585C>T		non_coding_transcript_exon_variant	Exon 15 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1629C>T		non_coding_transcript_exon_variant	Exon 13 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1657C>T		non_coding_transcript_exon_variant	Exon 16 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*660C>T		non_coding_transcript_exon_variant	Exon 14 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1166C>T		non_coding_transcript_exon_variant	Exon 14 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1004C>T		non_coding_transcript_exon_variant	Exon 15 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1147C>T		non_coding_transcript_exon_variant	Exon 14 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1715C>T		non_coding_transcript_exon_variant	Exon 14 of 16			ENSP00000502681.1
GARS1	ENST00000444666.6	n.*136C>T		3_prime_UTR_variant	Exon 15 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1429C>T		3_prime_UTR_variant	Exon 15 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*815C>T		3_prime_UTR_variant	Exon 15 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1053C>T		3_prime_UTR_variant	Exon 15 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*1585C>T		3_prime_UTR_variant	Exon 15 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1657C>T		3_prime_UTR_variant	Exon 16 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*660C>T		3_prime_UTR_variant	Exon 14 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1166C>T		3_prime_UTR_variant	Exon 14 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1004C>T		3_prime_UTR_variant	Exon 15 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1147C>T		3_prime_UTR_variant	Exon 14 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249582 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135408

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000521 AC: 76 AN: 1458190 Hom.: 0 Cov.: 29 AF XY: 0.0000510 AC XY: 37 AN XY: 725554

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000649

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74326

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Nov 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 572 of the GARS protein (p.Pro572Leu). This variant is present in population databases (rs764238525, gnomAD 0.003%). This missense change has been observed in individuals with autosomal dominant GARS-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 576818). 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 expected to disrupt GARS protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

May 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1715C>T (p.P572L) alteration is located in exon 14 (coding exon 14) of the GARS gene. This alteration results from a C to T substitution at nucleotide position 1715, causing the proline (P) at amino acid position 572 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

See cases Uncertain:1

Dec 14, 2023

Institute of Human Genetics, University Hospital Muenster

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PM2,PP3 -

not provided Uncertain:1

Jul 21, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GARS1 c.1715C>T; p.Pro572Leu variant (rs764238525), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is reported in ClinVar (Variation ID: 576818) and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 572 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL:0.941). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-9.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.79		Gain of sheet (P = 0.1945);
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
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: rs764238525; hg19: chr7-30668191;