7-30598875-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_002047.4(GARS1):​c.302G>C​(p.Arg101Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 6.8e-7 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Not reported in ClinVar
• 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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-30598875-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.302G>C	p.Arg101Pro	missense_variant	Exon 2 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.140G>C	p.Arg47Pro	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>C	p.Arg101Pro	missense_variant	Exon 2 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.302G>C	p.Arg101Pro	missense_variant	Exon 2 of 17			ENSP00000502513.1
GARS1	ENST00000675693.1	c.134G>C	p.Arg45Pro	missense_variant	Exon 3 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.101G>C	p.Arg34Pro	missense_variant	Exon 2 of 17			ENSP00000502296.1
GARS1	ENST00000674815	c.-68G>C		5_prime_UTR_variant	Exon 2 of 17			ENSP00000502799.1
GARS1	ENST00000674851	c.-68G>C		5_prime_UTR_variant	Exon 3 of 18			ENSP00000502451.1
GARS1	ENST00000675810.1	c.223-1072G>C		intron_variant	Intron 1 of 15			ENSP00000502743.1
GARS1	ENST00000444666.6	n.302G>C		non_coding_transcript_exon_variant	Exon 2 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.302G>C		non_coding_transcript_exon_variant	Exon 2 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.302G>C		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.302G>C		non_coding_transcript_exon_variant	Exon 2 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.302G>C		non_coding_transcript_exon_variant	Exon 2 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*172G>C		non_coding_transcript_exon_variant	Exon 3 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.302G>C		non_coding_transcript_exon_variant	Exon 2 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*172G>C		non_coding_transcript_exon_variant	Exon 3 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.302G>C		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.302G>C		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.302G>C		non_coding_transcript_exon_variant	Exon 2 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.302G>C		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.302G>C		non_coding_transcript_exon_variant	Exon 2 of 16			ENSP00000502681.1
GARS1	ENST00000675529.1	n.*172G>C		3_prime_UTR_variant	Exon 3 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*172G>C		3_prime_UTR_variant	Exon 3 of 19			ENSP00000501884.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.67	T
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.49
Sift	Benign	0.055	T
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.69		Loss of MoRF binding (P = 0.0047);
MVP		0.50
MPC		1.3
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-30638491;