chr7-30603537-G-A

Position:

• chr7-30603537-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_002047.4(GARS1):​c.700G>A​(p.Glu234Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,722 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 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.55

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 (MetaRNN=0.39966378).
• BP6: Variant 7-30603537-G-A is Benign according to our data. Variant chr7-30603537-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 476760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000789 (12/152116) while in subpopulation AFR AF= 0.000266 (11/41428). AF 95% confidence interval is 0.000149. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.700G>A	p.Glu234Lys	missense_variant	6/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.538G>A	p.Glu180Lys	missense_variant	6/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.700G>A	p.Glu234Lys	missense_variant	6/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.700G>A	p.Glu234Lys	missense_variant	6/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.598G>A	p.Glu200Lys	missense_variant	5/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.532G>A	p.Glu178Lys	missense_variant	7/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.499G>A	p.Glu167Lys	missense_variant	6/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.331G>A	p.Glu111Lys	missense_variant	6/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.331G>A	p.Glu111Lys	missense_variant	7/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.700G>A		non_coding_transcript_exon_variant	6/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*414G>A		non_coding_transcript_exon_variant	7/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.700G>A		non_coding_transcript_exon_variant	6/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.700G>A		non_coding_transcript_exon_variant	6/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.700G>A		non_coding_transcript_exon_variant	6/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*570G>A		non_coding_transcript_exon_variant	7/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.700G>A		non_coding_transcript_exon_variant	6/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*570G>A		non_coding_transcript_exon_variant	7/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.700G>A		non_coding_transcript_exon_variant	6/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*151G>A		non_coding_transcript_exon_variant	6/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.700G>A		non_coding_transcript_exon_variant	6/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*132G>A		non_coding_transcript_exon_variant	6/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.700G>A		non_coding_transcript_exon_variant	6/16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*414G>A		3_prime_UTR_variant	7/18			ENSP00000502408.1
GARS1	ENST00000675529.1	n.*570G>A		3_prime_UTR_variant	7/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*570G>A		3_prime_UTR_variant	7/19			ENSP00000501884.1
GARS1	ENST00000676164.1	n.*151G>A		3_prime_UTR_variant	6/17			ENSP00000501986.1
GARS1	ENST00000676259.1	n.*132G>A		3_prime_UTR_variant	6/17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000601 AC: 15 AN: 249404 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135338

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461606 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727120

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152116 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74298

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000534 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000910 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Distal spinal muscular atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 31, 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Charcot-Marie-Tooth disease type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 31, 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 31, 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.36	T
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.020	D
Sift4G	Benign	0.19	T
Polyphen		0.12	B
Vest4		0.73
MVP		0.81
MPC		0.57
ClinPred		0.14	T
GERP RS		5.7
Varity_R		0.75
gMVP		0.64

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: rs373326652; hg19: chr7-30643153; COSMIC: COSV66828691; COSMIC: COSV66828691;