7-30598875-G-T

Variant names:

• chr7-30598875-G-T
• rs200887429
• NM_002047.4:c.302G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM5 BS2

The NM_002047.4(GARS1):​c.302G>T​(p.Arg101Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R101H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.10

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 Likely_benign. Variant got -2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-30598875-G-A is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.302G>T	p.Arg101Leu	missense_variant	Exon 2 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.140G>T	p.Arg47Leu	missense_variant	Exon 2 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.302G>T	p.Arg101Leu	missense_variant	Exon 2 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.302G>T	p.Arg101Leu	missense_variant	Exon 2 of 17			ENSP00000502513.1
GARS1	ENST00000675693.1	c.134G>T	p.Arg45Leu	missense_variant	Exon 3 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.101G>T	p.Arg34Leu	missense_variant	Exon 2 of 17			ENSP00000502296.1
GARS1	ENST00000674815	c.-68G>T		5_prime_UTR_variant	Exon 2 of 17			ENSP00000502799.1
GARS1	ENST00000674851	c.-68G>T		5_prime_UTR_variant	Exon 3 of 18			ENSP00000502451.1
GARS1	ENST00000675810.1	c.223-1072G>T		intron_variant	Intron 1 of 15			ENSP00000502743.1
GARS1	ENST00000444666.6	n.302G>T		non_coding_transcript_exon_variant	Exon 2 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.302G>T		non_coding_transcript_exon_variant	Exon 2 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.302G>T		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.302G>T		non_coding_transcript_exon_variant	Exon 2 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.302G>T		non_coding_transcript_exon_variant	Exon 2 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*172G>T		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.302G>T		non_coding_transcript_exon_variant	Exon 2 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*172G>T		non_coding_transcript_exon_variant	Exon 3 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.302G>T		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.302G>T		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.302G>T		non_coding_transcript_exon_variant	Exon 2 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.302G>T		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.302G>T		non_coding_transcript_exon_variant	Exon 2 of 16			ENSP00000502681.1
GARS1	ENST00000675529.1	n.*172G>T		3_prime_UTR_variant	Exon 3 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*172G>T		3_prime_UTR_variant	Exon 3 of 19			ENSP00000501884.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249370 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135338

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000474 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2016

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.072
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.0091	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.25
Sift	Benign	0.36	T
Sift4G	Benign	0.83	T
Polyphen		0.040	B
Vest4		0.78
MutPred		0.55		Loss of MoRF binding (P = 0.028);
MVP		0.47
MPC		1.2
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		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: rs200887429; hg19: chr7-30638491;