rs951085877

Positions:

• chr7-30617201-C-A
• chr7-30617201-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002047.4(GARS1):​c.1282C>A​(p.Arg428Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,184 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.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1282C>A	p.Arg428Ser	missense_variant	10/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1120C>A	p.Arg374Ser	missense_variant	10/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1282C>A	p.Arg428Ser	missense_variant	10/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1282C>A	p.Arg428Ser	missense_variant	10/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1180C>A	p.Arg394Ser	missense_variant	9/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1114C>A	p.Arg372Ser	missense_variant	11/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1081C>A	p.Arg361Ser	missense_variant	10/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.913C>A	p.Arg305Ser	missense_variant	10/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.913C>A	p.Arg305Ser	missense_variant	11/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1282C>A		non_coding_transcript_exon_variant	10/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*996C>A		non_coding_transcript_exon_variant	11/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*382C>A		non_coding_transcript_exon_variant	11/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*620C>A		non_coding_transcript_exon_variant	11/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1282C>A		non_coding_transcript_exon_variant	10/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1152C>A		non_coding_transcript_exon_variant	11/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1282C>A		non_coding_transcript_exon_variant	10/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1224C>A		non_coding_transcript_exon_variant	12/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*227C>A		non_coding_transcript_exon_variant	10/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*733C>A		non_coding_transcript_exon_variant	10/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*571C>A		non_coding_transcript_exon_variant	11/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*714C>A		non_coding_transcript_exon_variant	10/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1282C>A		non_coding_transcript_exon_variant	10/16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*996C>A		3_prime_UTR_variant	11/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*382C>A		3_prime_UTR_variant	11/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*620C>A		3_prime_UTR_variant	11/18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*1152C>A		3_prime_UTR_variant	11/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1224C>A		3_prime_UTR_variant	12/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*227C>A		3_prime_UTR_variant	10/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*733C>A		3_prime_UTR_variant	10/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*571C>A		3_prime_UTR_variant	11/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*714C>A		3_prime_UTR_variant	10/17			ENSP00000501980.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

Gnomad4 AFR AF: 0.00

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

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.30	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.83		Gain of disorder (P = 0.0447);
MVP		0.83
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.97
gMVP		0.92

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: rs951085877; hg19: chr7-30656817;