5-168486503-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_002887.4(RARS1):c.5A>G(p.Asp2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,558,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D2D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

RARS1
NM_002887.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.73

Publications

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

RARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-168486503-A-G is Pathogenic according to our data. Variant chr5-168486503-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 162080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.30144027). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARS1	NM_002887.4 link	c.5A>G	p.Asp2Gly	missense_variant	Exon 1 of 15	ENST00000231572.8	NP_002878.2	P54136-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARS1	ENST00000231572.8 link	c.5A>G	p.Asp2Gly	missense_variant	Exon 1 of 15	1	NM_002887.4	ENSP00000231572.3		P54136-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000420

AC:

AN:

166652

AF XY:

0.0000455

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000900

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000277

AC:

AN:

1406664

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

694250

show subpopulations

African (AFR)

AF:

0.0000308

AC:

AN:

32508

American (AMR)

AF:

0.00

AC:

AN:

35866

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25192

East Asian (EAS)

AF:

0.0000270

AC:

AN:

37050

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1082536

Other (OTH)

AF:

0.00

AC:

AN:

58362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000328

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41546

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000450

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000280

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 9

Pathogenic:3

Nov 15, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The homozygous p.Asp2Gly variant in RARS was identified by our study in one individual with Hypomyelinating Leukodystrophy. This variant has been identified in the literature in the case of two affected homozygous siblings, one girl and one boy. It has also been identified in the case of three compound heterozygous affected probands, two sisters with the variants 45+1G>T, and one unrelated proband with the variant p.Cys32TrpfsTer39. Functional studies have shown that this variant causes severely reduced function of the protein complex (Nafisinia et al. 2017, PMID: 28905880; Wolf et al. 2014, PMID: 24777941). This variant has been identified in <0.01% (6/190228) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs672601372). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for Hypomyelinating Leukodystrophy in an autosomal recessive manner based on in vitro functional studies and multiple reports of individuals with this variant and Hypomyelinating Leukodrystrophy in the literature. -

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Apr 29, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Aug 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2 of the RARS protein (p.Asp2Gly). This variant is present in population databases (rs672601372, gnomAD 0.008%). This missense change has been observed in individual(s) with leukodystrophy (PMID: 24777941, 28905880). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162080). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.42

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.32

N;.

PhyloP100

2.7

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.5

N;.

REVEL

Pathogenic

0.74

Sift

Benign

0.18

T;.

Sift4G

Benign

0.51

T;T

Polyphen

0.0

B;.

Vest4

0.31

MutPred

0.22

Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);

MVP

0.57

MPC

0.17

ClinPred

0.18

GERP RS

3.6

PromoterAI

-0.22

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.58

gMVP

0.21

Mutation Taster

=94/6

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over