rs752464405

Positions:

• chr7-30628597-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002047.4(GARS1):​c.1737C>T​(p.Phe579Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GARS1 NM_002047.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.421

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 7-30628597-C-T is Benign according to our data. Variant chr7-30628597-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.421 with no splicing effect.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1737C>T	p.Phe579Phe	synonymous_variant	14/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1575C>T	p.Phe525Phe	synonymous_variant	14/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1737C>T	p.Phe579Phe	synonymous_variant	14/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1737C>T	p.Phe579Phe	synonymous_variant	14/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1635C>T	p.Phe545Phe	synonymous_variant	13/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1569C>T	p.Phe523Phe	synonymous_variant	15/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1536C>T	p.Phe512Phe	synonymous_variant	14/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1368C>T	p.Phe456Phe	synonymous_variant	14/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1368C>T	p.Phe456Phe	synonymous_variant	15/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*158C>T		non_coding_transcript_exon_variant	15/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1451C>T		non_coding_transcript_exon_variant	15/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*837C>T		non_coding_transcript_exon_variant	15/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1075C>T		non_coding_transcript_exon_variant	15/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*10C>T		non_coding_transcript_exon_variant	13/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1607C>T		non_coding_transcript_exon_variant	15/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*10C>T		non_coding_transcript_exon_variant	13/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1679C>T		non_coding_transcript_exon_variant	16/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*682C>T		non_coding_transcript_exon_variant	14/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1188C>T		non_coding_transcript_exon_variant	14/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1026C>T		non_coding_transcript_exon_variant	15/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1169C>T		non_coding_transcript_exon_variant	14/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1737C>T		non_coding_transcript_exon_variant	14/16			ENSP00000502681.1
GARS1	ENST00000444666.6	n.*158C>T		3_prime_UTR_variant	15/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1451C>T		3_prime_UTR_variant	15/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*837C>T		3_prime_UTR_variant	15/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1075C>T		3_prime_UTR_variant	15/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*10C>T		3_prime_UTR_variant	13/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1607C>T		3_prime_UTR_variant	15/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*10C>T		3_prime_UTR_variant	13/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1679C>T		3_prime_UTR_variant	16/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*682C>T		3_prime_UTR_variant	14/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1188C>T		3_prime_UTR_variant	14/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1026C>T		3_prime_UTR_variant	15/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1169C>T		3_prime_UTR_variant	14/17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152194 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: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249578 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135406

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460646 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 726614

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74336

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: 0.0000942

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 11, 2019	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	11
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs752464405; hg19: chr7-30668213;