7-30628642-T-C

Position:

• chr7-30628642-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002047.4(GARS1):​c.1782T>C​(p.His594His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,611,812 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: GARS1 NM_002047.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.44

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 7-30628642-T-C is Benign according to our data. Variant chr7-30628642-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 447372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.44 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1782T>C	p.His594His	synonymous_variant	14/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1620T>C	p.His540His	synonymous_variant	14/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1782T>C	p.His594His	synonymous_variant	14/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1782T>C	p.His594His	synonymous_variant	14/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1680T>C	p.His560His	synonymous_variant	13/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1614T>C	p.His538His	synonymous_variant	15/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1581T>C	p.His527His	synonymous_variant	14/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1413T>C	p.His471His	synonymous_variant	14/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1413T>C	p.His471His	synonymous_variant	15/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*203T>C		non_coding_transcript_exon_variant	15/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1496T>C		non_coding_transcript_exon_variant	15/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*882T>C		non_coding_transcript_exon_variant	15/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1120T>C		non_coding_transcript_exon_variant	15/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*55T>C		non_coding_transcript_exon_variant	13/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1652T>C		non_coding_transcript_exon_variant	15/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*55T>C		non_coding_transcript_exon_variant	13/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1724T>C		non_coding_transcript_exon_variant	16/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*727T>C		non_coding_transcript_exon_variant	14/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1233T>C		non_coding_transcript_exon_variant	14/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1071T>C		non_coding_transcript_exon_variant	15/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1214T>C		non_coding_transcript_exon_variant	14/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1782T>C		non_coding_transcript_exon_variant	14/16			ENSP00000502681.1
GARS1	ENST00000444666.6	n.*203T>C		3_prime_UTR_variant	15/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1496T>C		3_prime_UTR_variant	15/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*882T>C		3_prime_UTR_variant	15/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1120T>C		3_prime_UTR_variant	15/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*55T>C		3_prime_UTR_variant	13/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1652T>C		3_prime_UTR_variant	15/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*55T>C		3_prime_UTR_variant	13/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1724T>C		3_prime_UTR_variant	16/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*727T>C		3_prime_UTR_variant	14/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1233T>C		3_prime_UTR_variant	14/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1071T>C		3_prime_UTR_variant	15/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1214T>C		3_prime_UTR_variant	14/17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152234 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249568 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1459578 Hom.: 0 Cov.: 29 AF XY: 0.00000689 AC XY: 5 AN XY: 726164

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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. -

Charcot-Marie-Tooth disease type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.48
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs762072215; hg19: chr7-30668258;