7-30598809-G-A

Position:

• chr7-30598809-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP3_Moderate BP6 BS1 BS2

The NM_002047.4(GARS1):​c.236G>A​(p.Arg79Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,613,750 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).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 9.06

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 Benign. Variant got -7 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• BP6: Variant 7-30598809-G-A is Benign according to our data. Variant chr7-30598809-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188197.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000105 (16/152138) while in subpopulation NFE AF= 0.000176 (12/68024). AF 95% confidence interval is 0.000102. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.236G>A	p.Arg79Gln	missense_variant	2/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.74G>A	p.Arg25Gln	missense_variant	2/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.236G>A	p.Arg79Gln	missense_variant	2/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.236G>A	p.Arg79Gln	missense_variant	2/17			ENSP00000502513.1
GARS1	ENST00000675693.1	c.68G>A	p.Arg23Gln	missense_variant	3/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.35G>A	p.Arg12Gln	missense_variant	2/17			ENSP00000502296.1
GARS1	ENST00000674815	c.-134G>A		5_prime_UTR_variant	2/17			ENSP00000502799.1
GARS1	ENST00000674851	c.-134G>A		5_prime_UTR_variant	3/18			ENSP00000502451.1
GARS1	ENST00000675810.1	c.223-1138G>A		intron_variant				ENSP00000502743.1
GARS1	ENST00000444666.6	n.236G>A		non_coding_transcript_exon_variant	2/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.236G>A		non_coding_transcript_exon_variant	2/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.236G>A		non_coding_transcript_exon_variant	2/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.236G>A		non_coding_transcript_exon_variant	2/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.236G>A		non_coding_transcript_exon_variant	2/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*106G>A		non_coding_transcript_exon_variant	3/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.236G>A		non_coding_transcript_exon_variant	2/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*106G>A		non_coding_transcript_exon_variant	3/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.236G>A		non_coding_transcript_exon_variant	2/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.236G>A		non_coding_transcript_exon_variant	2/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.236G>A		non_coding_transcript_exon_variant	2/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.236G>A		non_coding_transcript_exon_variant	2/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.236G>A		non_coding_transcript_exon_variant	2/16			ENSP00000502681.1
GARS1	ENST00000675529.1	n.*106G>A		3_prime_UTR_variant	3/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*106G>A		3_prime_UTR_variant	3/19			ENSP00000501884.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000882 AC: 22 AN: 249462 Hom.: 0 AF XY: 0.0000886 AC XY: 12 AN XY: 135368

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: 0.000168

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000216 AC: 315 AN: 1461612 Hom.: 0 Cov.: 31 AF XY: 0.000191 AC XY: 139 AN XY: 727120

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000272

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74318

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000231 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000488 AC: 4

ExAC AF: 0.0000745 AC: 9

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	GARS1: BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 79 of the GARS protein (p.Arg79Gln). This variant is present in population databases (rs369466037, gnomAD 0.02%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 188197). 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 with a negative predictive value of 95%. 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.42	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.90
MVP		0.73
MPC		1.2
ClinPred		0.88	D
GERP RS		5.3
Varity_R		0.56
gMVP		0.69

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: rs369466037; hg19: chr7-30638425; COSMIC: COSV66828101; COSMIC: COSV66828101;