rs2305734

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 16/21 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. F397C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1712 hom., cov: 32)

Exomes 𝑓: 0.17 ( 22096 hom. )

Consequence

RARS1
NM_002887.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.39

Publications

23 publications found

Variant links:

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]

RARS1 Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 9
Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine

RARS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002887.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002887.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS1	NM_002887.4	MANE Select	c.1190T>A	p.Phe397Tyr	missense	Exon 10 of 15	NP_002878.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RARS1	ENST00000231572.8	TSL:1 MANE Select	c.1190T>A	p.Phe397Tyr	missense	Exon 10 of 15	ENSP00000231572.3	P54136-1
RARS1	ENST00000922755.1		c.1214T>A	p.Phe405Tyr	missense	Exon 10 of 15	ENSP00000592814.1
RARS1	ENST00000953515.1		c.1190T>A	p.Phe397Tyr	missense	Exon 10 of 16	ENSP00000623574.1

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19782

AN:

152014

Hom.:

1711

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.138

AC:

31307

AN:

227456

AF XY:

0.140

show subpopulations

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 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.:

AF XY:

0.166

AC XY:

117867

AN XY:

709822

show subpopulations

African (AFR)

AF:

0.0267

AC:

853

AN:

31984

American (AMR)

AF:

0.0736

AC:

2808

AN:

38146

Ashkenazi Jewish (ASJ)

AF:

0.150

AC:

3783

AN:

25274

East Asian (EAS)

AF:

0.0852

AC:

3330

AN:

39078

South Asian (SAS)

AF:

0.0616

AC:

4984

AN:

80942

European-Finnish (FIN)

AF:

0.199

AC:

10563

AN:

53172

Middle Eastern (MID)

AF:

0.0538

AC:

306

AN:

5690

European-Non Finnish (NFE)

AF:

0.187

AC:

204613

AN:

1093324

Other (OTH)

AF:

0.153

AC:

9054

AN:

59296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

9233

18466

27700

36933

46166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6876

13752

20628

27504

34380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.130

AC:

19782

AN:

152132

Hom.:

1712

Cov.:

AF XY:

0.127

AC XY:

9436

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0321

AC:

1333

AN:

41520

American (AMR)

AF:

0.114

AC:

1739

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.152

AC:

528

AN:

3468

East Asian (EAS)

AF:

0.0629

AC:

326

AN:

5184

South Asian (SAS)

AF:

0.0628

AC:

303

AN:

4822

European-Finnish (FIN)

AF:

0.192

AC:

2026

AN:

10566

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.192

AC:

13032

AN:

67978

Other (OTH)

AF:

0.121

AC:

255

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

864

1728

2593

3457

4321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.171

Hom.:

794

Bravo

AF:

0.119

Asia WGS

AF:

0.0610

AC:

213

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.091

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0012

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

2.4

PrimateAI

Benign

0.28

PROVEAN

Benign

0.54

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

1.0

Varity_R

0.19

gMVP

0.46

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over