rs139644798

chr5-168510601-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

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). Synonymous variant affecting the same amino acid position (i.e. S456S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (2 hom.)
• Consequence: RARS1 NM_002887.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1 B:1
• Conservation: PhyloP100: 7.45

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]

ACMG classification

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, Pathogenic=1, Benign=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32903418).. Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARS1	NM_002887.4	c.1367C>T	p.Ser456Leu	missense_variant	12/15	ENST00000231572.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152036 Hom.: 0 Cov.: 32

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: 92 AN: 244948 Hom.: 2 AF XY: 0.000355 AC XY: 47 AN XY: 132314

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.: 2 Cov.: 30 AF XY: 0.000459 AC XY: 332 AN XY: 723822

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: 67 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31 AN XY: 74380

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.: 1

Bravo AF: 0.000321

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000478 AC: 58

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

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	-	- -
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. -
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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 20, 2019	- -
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	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	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. -

not provided Pathogenic:2 Benign: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	Invitae	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	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.0041	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.88	P
Vest4		0.50
MVP		0.77
MPC		0.13
ClinPred		0.27	T
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

Other links and lift over

dbSNP: rs139644798; hg19: chr5-167937606; COSMIC: COSV51564187; COSMIC: COSV51564187;