5-168486505-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002887.4(RARS1):c.7G>C(p.Val3Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000178 in 1,406,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. V3I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: RARS1 NM_002887.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.08

Genes affected

RARS1 (HGNC:9870): (arginyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Arginyl-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09059194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS1	NM_002887.4	c.7G>C	p.Val3Leu	missense_variant	1/15	ENST00000231572.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARS1	ENST00000231572.8	c.7G>C	p.Val3Leu	missense_variant	1/15	1	NM_002887.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000180 AC: 3 AN: 166308 Hom.: 0 AF XY: 0.0000114 AC XY: 1 AN XY: 87782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000401

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: 0.0000301

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 25 AN: 1406510 Hom.: 0 Cov.: 45 AF XY: 0.0000202 AC XY: 14 AN XY: 694244

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.0000558

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: 0.0000203

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000307 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.7G>C (p.V3L) alteration is located in exon 1 (coding exon 1) of the RARS gene. This alteration results from a G to C substitution at nucleotide position 7, causing the valine (V) at amino acid position 3 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 27, 2022

This variant is present in population databases (rs244903, gnomAD 0.004%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with RARS-related conditions. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3 of the RARS protein (p.Val3Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	15
Dann	Benign	0.75
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.091	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.23	N;.
REVEL	Benign	0.094
Sift	Benign	0.35	T;.
Sift4G	Benign	0.38	T;T
Polyphen		0.0	B;.
Vest4		0.12
MutPred		0.14		Gain of disorder (P = 0.094);Gain of disorder (P = 0.094);
MVP		0.60
MPC		0.12
ClinPred		0.18	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.14

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: rs244903; hg19: chr5-167913510;