rs181251337

Variant names:

• chr7-30633852-G-A
• rs181251337
• NM_002047.4:c.2212G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002047.4(GARS1):​c.2212G>A​(p.Glu738Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,598,594 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.76

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030388266).
• BP6: Variant 7-30633852-G-A is Benign according to our data. Variant chr7-30633852-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 360019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30633852-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000993 (15/151036) while in subpopulation EAS AF= 0.00237 (12/5072). AF 95% confidence interval is 0.00136. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.2212G>A	p.Glu738Lys	missense_variant	Exon 17 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.2050G>A	p.Glu684Lys	missense_variant	Exon 17 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.2212G>A	p.Glu738Lys	missense_variant	Exon 17 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.2230G>A	p.Glu744Lys	missense_variant	Exon 17 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.2110G>A	p.Glu704Lys	missense_variant	Exon 16 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.2044G>A	p.Glu682Lys	missense_variant	Exon 18 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.2011G>A	p.Glu671Lys	missense_variant	Exon 17 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1843G>A	p.Glu615Lys	missense_variant	Exon 17 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1843G>A	p.Glu615Lys	missense_variant	Exon 18 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*633G>A		non_coding_transcript_exon_variant	Exon 18 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1926G>A		non_coding_transcript_exon_variant	Exon 18 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*2017G>A		non_coding_transcript_exon_variant	Exon 17 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1550G>A		non_coding_transcript_exon_variant	Exon 18 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*485G>A		non_coding_transcript_exon_variant	Exon 16 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*2082G>A		non_coding_transcript_exon_variant	Exon 18 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*391G>A		non_coding_transcript_exon_variant	Exon 15 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*2154G>A		non_coding_transcript_exon_variant	Exon 19 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*1157G>A		non_coding_transcript_exon_variant	Exon 17 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1663G>A		non_coding_transcript_exon_variant	Exon 17 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1501G>A		non_coding_transcript_exon_variant	Exon 18 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1644G>A		non_coding_transcript_exon_variant	Exon 17 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.*297G>A		non_coding_transcript_exon_variant	Exon 16 of 16			ENSP00000502681.1
GARS1	ENST00000444666.6	n.*633G>A		3_prime_UTR_variant	Exon 18 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1926G>A		3_prime_UTR_variant	Exon 18 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*2017G>A		3_prime_UTR_variant	Exon 17 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1550G>A		3_prime_UTR_variant	Exon 18 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*485G>A		3_prime_UTR_variant	Exon 16 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*2082G>A		3_prime_UTR_variant	Exon 18 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*391G>A		3_prime_UTR_variant	Exon 15 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*2154G>A		3_prime_UTR_variant	Exon 19 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*1157G>A		3_prime_UTR_variant	Exon 17 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1663G>A		3_prime_UTR_variant	Exon 17 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1501G>A		3_prime_UTR_variant	Exon 18 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1644G>A		3_prime_UTR_variant	Exon 17 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.*297G>A		3_prime_UTR_variant	Exon 16 of 16			ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.0000994 AC: 15 AN: 150918 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00236

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000164 AC: 41 AN: 249272 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00217

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000116 AC: 168 AN: 1447558 Hom.: 1 Cov.: 41 AF XY: 0.0000958 AC XY: 69 AN XY: 720330

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00419

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000505

GnomAD4 genome AF: 0.0000993 AC: 15 AN: 151036 Hom.: 0 Cov.: 31 AF XY: 0.0000814 AC XY: 6 AN XY: 73752

Gnomad4 AFR AF: 0.0000487

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00237

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000476

Bravo AF: 0.0000680

ExAC AF: 0.000215 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Feb 28, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Distal spinal muscular atrophy Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Charcot-Marie-Tooth disease type 2 Benign:1

Jan 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 09, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.030	T
MetaSVM	Uncertain	-0.12	T
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.49	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.064	T
Polyphen		0.76	P
Vest4		0.70
MVP		0.87
MPC		0.50
ClinPred		0.16	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.74

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: rs181251337; hg19: chr7-30673468;