rs370608239

Positions:

• chr7-30628576-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_002047.4(GARS1):​c.1716G>A​(p.Pro572Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,610,862 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign 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 (2 hom.)
• Consequence: GARS1 NM_002047.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.514

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 7-30628576-G-A is Benign according to our data. Variant chr7-30628576-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194367.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6, Benign=2}. Variant chr7-30628576-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.514 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000112 (17/152194) while in subpopulation EAS AF= 0.000961 (5/5202). AF 95% confidence interval is 0.000379. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1716G>A	p.Pro572Pro	synonymous_variant	14/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1554G>A	p.Pro518Pro	synonymous_variant	14/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1716G>A	p.Pro572Pro	synonymous_variant	14/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1716G>A	p.Pro572Pro	synonymous_variant	14/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1614G>A	p.Pro538Pro	synonymous_variant	13/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1548G>A	p.Pro516Pro	synonymous_variant	15/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1515G>A	p.Pro505Pro	synonymous_variant	14/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1347G>A	p.Pro449Pro	synonymous_variant	14/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1347G>A	p.Pro449Pro	synonymous_variant	15/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*137G>A		non_coding_transcript_exon_variant	15/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1430G>A		non_coding_transcript_exon_variant	15/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*816G>A		non_coding_transcript_exon_variant	15/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1054G>A		non_coding_transcript_exon_variant	15/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1630G>A		non_coding_transcript_exon_variant	13/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1586G>A		non_coding_transcript_exon_variant	15/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1630G>A		non_coding_transcript_exon_variant	13/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1658G>A		non_coding_transcript_exon_variant	16/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*661G>A		non_coding_transcript_exon_variant	14/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1167G>A		non_coding_transcript_exon_variant	14/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1005G>A		non_coding_transcript_exon_variant	15/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1148G>A		non_coding_transcript_exon_variant	14/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1716G>A		non_coding_transcript_exon_variant	14/16			ENSP00000502681.1
GARS1	ENST00000444666.6	n.*137G>A		3_prime_UTR_variant	15/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1430G>A		3_prime_UTR_variant	15/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*816G>A		3_prime_UTR_variant	15/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1054G>A		3_prime_UTR_variant	15/18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*1586G>A		3_prime_UTR_variant	15/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1658G>A		3_prime_UTR_variant	16/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*661G>A		3_prime_UTR_variant	14/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1167G>A		3_prime_UTR_variant	14/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1005G>A		3_prime_UTR_variant	15/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1148G>A		3_prime_UTR_variant	14/17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000216 AC: 54 AN: 249584 Hom.: 0 AF XY: 0.000207 AC XY: 28 AN XY: 135410

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00222

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000221 AC: 323 AN: 1458668 Hom.: 2 Cov.: 29 AF XY: 0.000233 AC XY: 169 AN XY: 725802

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00452

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000961

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000680

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 06, 2024	- -
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	GeneDx	Oct 06, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 02, 2014

- -

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Distal spinal muscular atrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.7
DANN	Benign	0.71

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: rs370608239; hg19: chr7-30668192;