rs376772628

Variant names:

• chr7-30601193-G-A
• rs376772628
• NM_002047.4:c.562G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_002047.4(GARS1):​c.562G>A​(p.Val188Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,630 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 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 9.89

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 7-30601193-G-A is Benign according to our data. Variant chr7-30601193-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 431819.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000657 (10/152146) while in subpopulation NFE AF= 0.000103 (7/68014). AF 95% confidence interval is 0.0000477. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.562G>A	p.Val188Ile	missense_variant	Exon 4 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.400G>A	p.Val134Ile	missense_variant	Exon 4 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.562G>A	p.Val188Ile	missense_variant	Exon 4 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.562G>A	p.Val188Ile	missense_variant	Exon 4 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.460G>A	p.Val154Ile	missense_variant	Exon 3 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.394G>A	p.Val132Ile	missense_variant	Exon 5 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.361G>A	p.Val121Ile	missense_variant	Exon 4 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.193G>A	p.Val65Ile	missense_variant	Exon 4 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.193G>A	p.Val65Ile	missense_variant	Exon 5 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.562G>A		non_coding_transcript_exon_variant	Exon 4 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*276G>A		non_coding_transcript_exon_variant	Exon 5 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.562G>A		non_coding_transcript_exon_variant	Exon 4 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.562G>A		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.562G>A		non_coding_transcript_exon_variant	Exon 4 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*432G>A		non_coding_transcript_exon_variant	Exon 5 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.562G>A		non_coding_transcript_exon_variant	Exon 4 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*432G>A		non_coding_transcript_exon_variant	Exon 5 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.562G>A		non_coding_transcript_exon_variant	Exon 4 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.562G>A		non_coding_transcript_exon_variant	Exon 4 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.562G>A		non_coding_transcript_exon_variant	Exon 4 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.492G>A		non_coding_transcript_exon_variant	Exon 4 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.562G>A		non_coding_transcript_exon_variant	Exon 4 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*276G>A		3_prime_UTR_variant	Exon 5 of 18			ENSP00000502408.1
GARS1	ENST00000675529.1	n.*432G>A		3_prime_UTR_variant	Exon 5 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*432G>A		3_prime_UTR_variant	Exon 5 of 19			ENSP00000501884.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000103

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000100 AC: 25 AN: 249510 Hom.: 0 AF XY: 0.000126 AC XY: 17 AN XY: 135370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000109 AC: 159 AN: 1461484 Hom.: 0 Cov.: 30 AF XY: 0.000102 AC XY: 74 AN XY: 727046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

Gnomad4 AFR AF: 0.00

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: 0.000103

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.0000575 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000993 AC: 12

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Aug 30, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The V188I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V188I variant is observed in 7/30,782 (0.02%) alleles from individuals of South Asian background, in the ExAC dataset (Lek et al., 2016). The V188I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Jun 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 11, 2024

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Distal spinal muscular atrophy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 2 Benign:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Neuronopathy, distal hereditary motor, type 5A Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.0091	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.66
MVP		0.71
MPC		1.0
ClinPred		0.20	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.89

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: rs376772628; hg19: chr7-30640809;