Genetic Variant RARS1:p.Asp2Glu (chr5-168486504-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_002887.4(RARS1):c.6C>G(p.Asp2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RARS1
NM_002887.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.204

Publications

0 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, Orphanet

RARS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.6C>G	p.Asp2Glu	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.6C>G	p.Asp2Glu	missense	Exon 1 of 15	ENSP00000231572.3	P54136-1
RARS1	ENST00000922755.1		c.6C>G	p.Asp2Glu	missense	Exon 1 of 15	ENSP00000592814.1
RARS1	ENST00000953515.1		c.6C>G	p.Asp2Glu	missense	Exon 1 of 16	ENSP00000623574.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1406766

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

694312

African (AFR)

AF:

0.00

AC:

AN:

32516

American (AMR)

AF:

0.00

AC:

AN:

35868

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25198

East Asian (EAS)

AF:

0.00

AC:

AN:

37064

South Asian (SAS)

AF:

0.00

AC:

AN:

79846

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082582

Other (OTH)

AF:

0.00

AC:

AN:

58364

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

5.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.27

M_CAP

Benign

0.0096

MetaRNN

Benign

0.068

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.14

PhyloP100

0.20

PrimateAI

Benign

0.43

PROVEAN

Benign

0.010

REVEL

Benign

0.084

Sift

Benign

0.49

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.11

MutPred

0.23

Gain of sheet (P = 0.0266)

MVP

0.44

MPC

0.12

ClinPred

0.20

GERP RS

0.53

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.20

gMVP

0.093

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.83

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.83

Position offset: 0

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over