rs139644798

Positions:

chr5-168510601-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_002887.4(RARS1):c.1367C>T(p.Ser456Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,607,570 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 2 hom. )

Consequence

RARS1
NM_002887.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:1B:1

Conservation

PhyloP100: 7.45

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5

Variant 5-168510601-C-T is Pathogenic according to our data. Variant chr5-168510601-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265854.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=7, Benign=1, Uncertain_significance=2, Pathogenic=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.32903418). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RARS1	NM_002887.4 linkuse as main transcript	c.1367C>T	p.Ser456Leu	missense_variant	12/15	ENST00000231572.8	NP_002878.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RARS1	ENST00000231572.8 linkuse as main transcript	c.1367C>T	p.Ser456Leu	missense_variant	12/15	1	NM_002887.4	ENSP00000231572	P1	P54136-1
RARS1	ENST00000520013.5 linkuse as main transcript	c.*868C>T		3_prime_UTR_variant, NMD_transcript_variant	11/14	2		ENSP00000429030

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000376

AC:

AN:

244948

Hom.:

AF XY:

0.000355

AC XY:

AN XY:

132314

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.0000619

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000348

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.000579

Gnomad OTH exome

AF:

0.000667

GnomAD4 exome

AF:

0.000424

AC:

617

AN:

1455414

Hom.:

Cov.:

AF XY:

0.000459

AC XY:

332

AN XY:

723822

show subpopulations

Gnomad4 AFR exome

AF:

0.000302

Gnomad4 AMR exome

AF:

0.0000937

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000177

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000502

Gnomad4 OTH exome

AF:

0.000266

GnomAD4 genome

AF:

0.000440

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000779

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000660

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000478

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 9

Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 15, 2021	- -
Pathogenic, no assertion criteria provided	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 20, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with hypomyelinating leukodystrophy, 9 (MIM#616140). Toxic gain of function has also been suggested (PMID: 31737794). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (119 heterozygotes, 2 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located adjacent in the annotated KMSKS motif, near a catalytic domain (PMID: 33515434, PMID: 28905880). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed in two compound heterozygous individuals with a hypomyelination disorder or mild hypomyelinating leukodystrophy. In one individual, the second variant was either due to a de novo event or non-paternity (PMID: 28905880, PMID: 31814314, ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cells demonstrated protein mislocalization, increases in punctate structures and decreased phosphorylation of ribosomal S6 protein (PMID: 31737794), whereas transfected E.coli cells showed decreased aminoacetylation activity (PMID: 33515434). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 14, 2023	Variant summary: RARS c.1367C>T (p.Ser456Leu) results in a non-conservative amino acid change located in the Arginyl-tRNA synthetase, catalytic core domain (IPR035684) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 244948 control chromosomes in the gnomAD database, including 2 homozygotes. c.1367C>T has been reported in the literature in compound heterozygous individuals affected with PelizaeusMerzbacher disease (Nafinisia_2017) or mild hypomyelinating leukodystrophy (Mendes_2020), and the former had a truncating variant in trans. These data indicate that the variant is likely associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in reduced aminoacylation activity and phosphorylation of ribosomal S6 protein, as well as disrupting protein localization and formation of myelin structures (Matsumoto_2019, Li_2021). The following publications have been ascertained in the context of this evaluation (PMID: 28905880, 31814314, 33515434, 31737794). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=7) or benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.1367C>T p.Ser456Leu variant in the RARS1 has been reported as likely pathogenic and pathogenic, and observed in two compound heterozygous individuals with a hypomyelination disorder or mild hypomyelinating leukodystrophy Nafisinia, Michael et al.,2017. No published segregation evidence has been identified for this variant. This variant has moderate functional evidence supporting abnormal protein function Matsumoto, Naoto et al.,2019. This variant is reported with the allele frequency 0.04% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Pathogenic/ Likely Pathogenic multiple submissions. The amino acid Serine at position 456 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ser456Leu in RARS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265854, PMID:28905880). In silico tool predictions suggest damaging effect of the variant on gene or gene product(3CNET: 0.777>=0.75). A missense variant is a common mechanism associated with Leukodystrophy, hypomyelinating, 9. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0005004). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 13, 2020	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3_MOD,PS4_MOD,PM3,PP3. -

not provided

Pathogenic:2Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2020

The c.1367C>T (p.S456L) alteration is located in exon 12 (coding exon 12) of the RARS gene. This alteration results from a C to T substitution at nucleotide position 1367, causing the serine (S) at amino acid position 456 to be replaced by a leucine (L). This variant and a frameshift variant were identified in one individual with microcephaly, nystagmus, blindness, cognitive impairment, focal epilepsy, corpus callosum hypoplasia, and diffuse dysmyelination/hypomyelination of the central white matter; p.S456L was maternally inherited while the frameshift variant was not detected in either parent (Nafisinia, 2017). This variant was also identified with a another missense variant in a mildly affected individual with onset at two years of age and ability to walk without support; this individual did not have nystagmus, microcephaly, epilepsy, feeding difficulties, hypomyelination, or brain atrophy (Mendes, 2020). This variant formed punctate structures in 25% of cells compared wildtype in COS7 cells and failed to exhibit differentiated phenotypes with myelin web-like structures in FBD-102b cells (Matsumoto, 2019). The p.S456L alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.33

MetaSVM

Uncertain

-0.0041

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.33

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.88

Vest4

0.50

MVP

0.77

MPC

0.13

ClinPred

0.27

GERP RS

5.0

Varity_R

0.92

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over