chr5-168486505-G-A

Variant names:

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.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. 15/21 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. 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.08

Publications

49 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=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 VariationId 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.

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.7G>A	p.Val3Ile	missense	Exon 1 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.7G>A	p.Val3Ile	missense	Exon 1 of 15	ENSP00000231572.3	P54136-1
RARS1	ENST00000922755.1		c.7G>A	p.Val3Ile	missense	Exon 1 of 15	ENSP00000592814.1
RARS1	ENST00000953515.1		c.7G>A	p.Val3Ile	missense	Exon 1 of 16	ENSP00000623574.1

Frequencies

GnomAD3 genomes

AF:

0.628

AC:

95388

AN:

151908

Hom.:

30686

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.602

AC:

100196

AN:

166308

AF XY:

0.588

show subpopulations

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 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.:

AF XY:

0.563

AC XY:

390909

AN XY:

694020

show subpopulations

African (AFR)

AF:

0.740

AC:

24012

AN:

32456

American (AMR)

AF:

0.728

AC:

26114

AN:

35868

Ashkenazi Jewish (ASJ)

AF:

0.486

AC:

12253

AN:

25192

East Asian (EAS)

AF:

0.880

AC:

32558

AN:

36986

South Asian (SAS)

AF:

0.506

AC:

40414

AN:

79818

European-Finnish (FIN)

AF:

0.567

AC:

28087

AN:

49558

Middle Eastern (MID)

AF:

0.578

AC:

3291

AN:

5694

European-Non Finnish (NFE)

AF:

0.550

AC:

595535

AN:

1082064

Other (OTH)

AF:

0.589

AC:

34354

AN:

58348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

16930

33859

50789

67718

84648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17066

34132

51198

68264

85330

<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:

0.628

AC:

95487

AN:

152026

Hom.:

30732

Cov.:

AF XY:

0.631

AC XY:

46900

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.739

AC:

30650

AN:

41470

American (AMR)

AF:

0.687

AC:

10481

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.497

AC:

1723

AN:

3466

East Asian (EAS)

AF:

0.877

AC:

4527

AN:

5162

South Asian (SAS)

AF:

0.512

AC:

2467

AN:

4816

European-Finnish (FIN)

AF:

0.569

AC:

6019

AN:

10576

Middle Eastern (MID)

AF:

0.589

AC:

172

AN:

292

European-Non Finnish (NFE)

AF:

0.554

AC:

37677

AN:

67974

Other (OTH)

AF:

0.609

AC:

1283

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1773

3546

5319

7092

8865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

766

1532

2298

3064

3830

<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:

0.576

Hom.:

111917

Bravo

AF:

0.650

Asia WGS

AF:

0.696

AC:

2418

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypomyelinating leukodystrophy 9 (2)

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.14

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.43

MetaRNN

Benign

9.7e-7

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

4.1

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.10

REVEL

Benign

0.10

Sift

Benign

0.19

Sift4G

Benign

0.21

PromoterAI

-0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.095

Mutation Taster

=297/3

polymorphism (auto)

(source)

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

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