5-168506153-T-A

Position:

• chr5-168506153-T-A

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.1190T>A​(p.Phe397Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,579,038 control chromosomes in the GnomAD database, including 23,808 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1712 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22096 hom.)
• Consequence: RARS1 NM_002887.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.39

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=0.001244545).
• BP6: Variant 5-168506153-T-A is Benign according to our data. Variant chr5-168506153-T-A is described in ClinVar as [Benign]. Clinvar id is 380055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS1	NM_002887.4	c.1190T>A	p.Phe397Tyr	missense_variant	10/15	ENST00000231572.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARS1	ENST00000231572.8	c.1190T>A	p.Phe397Tyr	missense_variant	10/15	1	NM_002887.4	P1
RARS1	ENST00000520013.5	c.*691T>A		3_prime_UTR_variant, NMD_transcript_variant	9/14	2

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19782 AN: 152014 Hom.: 1711 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0627

Gnomad SAS AF: 0.0622

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.138 AC: 31307 AN: 227456 Hom.: 2718 AF XY: 0.140 AC XY: 17178 AN XY: 123040

Gnomad AFR exome AF: 0.0322

Gnomad AMR exome AF: 0.0690

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.0549

Gnomad SAS exome AF: 0.0606

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.168 AC: 240294 AN: 1426906 Hom.: 22096 Cov.: 31 AF XY: 0.166 AC XY: 117867 AN XY: 709822

Gnomad4 AFR exome AF: 0.0267

Gnomad4 AMR exome AF: 0.0736

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.0852

Gnomad4 SAS exome AF: 0.0616

Gnomad4 FIN exome AF: 0.199

Gnomad4 NFE exome AF: 0.187

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.130 AC: 19782 AN: 152132 Hom.: 1712 Cov.: 32 AF XY: 0.127 AC XY: 9436 AN XY: 74376

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.0629

Gnomad4 SAS AF: 0.0628

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.121

Alfa AF: 0.171 Hom.: 794

Bravo AF: 0.119

TwinsUK AF: 0.190 AC: 704

ALSPAC AF: 0.191 AC: 736

ESP6500AA AF: 0.0356 AC: 157

ESP6500EA AF: 0.172 AC: 1483

ExAC AF: 0.137 AC: 16652

Asia WGS AF: 0.0610 AC: 213 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2016

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.42
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.10
MPC		0.15
ClinPred		0.0020	T
GERP RS		3.1
Varity_R		0.19
gMVP		0.46

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: rs2305734; hg19: chr5-167933158; COSMIC: COSV51563641; COSMIC: COSV51563641;