rs863223328

chr7-30595016-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_002047.4(GARS1):c.95T>C(p.Leu32Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000701 in 1,426,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.851

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-DT (HGNC:48951): (GARS1 divergent transcript)

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057976395).
• BP6: Variant 7-30595016-T-C is Benign according to our data. Variant chr7-30595016-T-C is described in ClinVar as [Benign]. Clinvar id is 217861.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GARS1	NM_002047.4	c.95T>C	p.Leu32Pro	missense_variant	1/17	ENST00000389266.8
GARS1	NM_001316772.1	c.-68T>C		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GARS1	ENST00000389266.8	c.95T>C	p.Leu32Pro	missense_variant	1/17	1	NM_002047.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000520 AC: 1 AN: 192172 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 106338

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: 0.0000116

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000701 AC: 10 AN: 1426720 Hom.: 0 Cov.: 31 AF XY: 0.00000565 AC XY: 4 AN XY: 708488

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: 0.00000907

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease Benign:1

Benign, no assertion criteria provided

research

Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust

Oct 01, 2014

Present in only four out of five affected family members, seen in one unaffected family member. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	6.9
Dann	Benign	0.50
DEOGEN2	Benign	0.064	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.37	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.36	N;.
REVEL	Benign	0.096
Sift	Benign	0.28	T;.
Sift4G	Benign	0.074	T;T
Polyphen		0.0	B;.
Vest4		0.067
MutPred		0.30		Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);
MVP		0.093
MPC		0.56
ClinPred		0.066	T
GERP RS		-0.31
Varity_R		0.059
gMVP		0.30

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: rs863223328; hg19: chr7-30634632;