rs244903

chr5-168486505-G-Achr5-168486505-G-Cchr5-168486505-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002887.4(RARS1):c.7G>A(p.Val3Ile) variant causes a missense change. The variant allele was found at a frequency of 0.573 in 1,558,010 control chromosomes in the GnomAD database, including 260,198 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.63 (30732 hom., cov: 32)
  • Exomes 𝑓: 0.57 (229466 hom.)
• Consequence: RARS1 NM_002887.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.688819E-7).
• BP6: Variant 5-168486505-G-A is Benign according to our data. Variant chr5-168486505-G-A is described in ClinVar as [Benign]. Clinvar id is 380030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS1	NM_002887.4	c.7G>A	p.Val3Ile	missense_variant	1/15	ENST00000231572.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARS1	ENST00000231572.8	c.7G>A	p.Val3Ile	missense_variant	1/15	1	NM_002887.4	P1

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95388 AN: 151908 Hom.: 30686 Cov.: 32

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.539

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.877

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.605

GnomAD3 exomes AF: 0.602 AC: 100196 AN: 166308 Hom.: 31542 AF XY: 0.588 AC XY: 51648 AN XY: 87782

Gnomad AFR exome AF: 0.737

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.478

Gnomad EAS exome AF: 0.874

Gnomad SAS exome AF: 0.501

Gnomad FIN exome AF: 0.566

Gnomad NFE exome AF: 0.542

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.567 AC: 796618 AN: 1405984 Hom.: 229466 Cov.: 45 AF XY: 0.563 AC XY: 390909 AN XY: 694020

Gnomad4 AFR exome AF: 0.740

Gnomad4 AMR exome AF: 0.728

Gnomad4 ASJ exome AF: 0.486

Gnomad4 EAS exome AF: 0.880

Gnomad4 SAS exome AF: 0.506

Gnomad4 FIN exome AF: 0.567

Gnomad4 NFE exome AF: 0.550

Gnomad4 OTH exome AF: 0.589

GnomAD4 genome AF: 0.628 AC: 95487 AN: 152026 Hom.: 30732 Cov.: 32 AF XY: 0.631 AC XY: 46900 AN XY: 74290

Gnomad4 AFR AF: 0.739

Gnomad4 AMR AF: 0.687

Gnomad4 ASJ AF: 0.497

Gnomad4 EAS AF: 0.877

Gnomad4 SAS AF: 0.512

Gnomad4 FIN AF: 0.569

Gnomad4 NFE AF: 0.554

Gnomad4 OTH AF: 0.609

Alfa AF: 0.565 Hom.: 55357

Bravo AF: 0.650

TwinsUK AF: 0.546 AC: 2026

ALSPAC AF: 0.561 AC: 2163

ESP6500AA AF: 0.753 AC: 3246

ESP6500EA AF: 0.553 AC: 4685

ExAC AF: 0.503 AC: 49127

Asia WGS AF: 0.696 AC: 2418 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Benign	0.90
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	9.7e-7	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.10	N;.
REVEL	Benign	0.10
Sift	Benign	0.19	T;.
Sift4G	Benign	0.21	T;T
Polyphen		0.0010	B;.
Vest4		0.13
MPC		0.10
ClinPred		0.042	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.095

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV51562223; COSMIC: COSV51562223;