rs139644798

Variant names:

• chr5-168510601-C-T
• rs139644798
• NM_002887.4:c.1367C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BS1_Supporting 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:9 U:2 B:2
• 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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32903418).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00044 (67/152156) while in subpopulation NFE AF = 0.000779 (53/67994). AF 95% confidence interval is 0.000612. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARS1	NM_002887.4	c.1367C>T	p.Ser456Leu	missense_variant	Exon 12 of 15	ENST00000231572.8	NP_002878.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARS1	ENST00000231572.8	c.1367C>T	p.Ser456Leu	missense_variant	Exon 12 of 15	1	NM_002887.4	ENSP00000231572.3
RARS1	ENST00000520013.5	n.*868C>T		non_coding_transcript_exon_variant	Exon 11 of 14	2		ENSP00000429030.1
RARS1	ENST00000520013.5	n.*868C>T		3_prime_UTR_variant	Exon 11 of 14	2		ENSP00000429030.1

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

GnomAD2 exomes AF: 0.000376 AC: 92 AN: 244948 AF XY: 0.000355

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 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 AC: 10 AN: 33064

Gnomad4 AMR exome AF: 0.0000937 AC: 4 AN: 42682

Gnomad4 ASJ exome AF: 0.0000384 AC: 1 AN: 26020

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39544

Gnomad4 SAS exome AF: 0.000177 AC: 15 AN: 84512

Gnomad4 FIN exome AF: 0.000150 AC: 8 AN: 53364

Gnomad4 NFE exome AF: 0.000502 AC: 557 AN: 1110312

Gnomad4 Remaining exome AF: 0.000266 AC: 16 AN: 60158

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 AC: 0.0000481719 AN: 0.0000481719

Gnomad4 AMR AF: 0.000262 AC: 0.000261506 AN: 0.000261506

Gnomad4 ASJ AF: 0.000288 AC: 0.000288184 AN: 0.000288184

Gnomad4 EAS AF: 0.000386 AC: 0.000385654 AN: 0.000385654

Gnomad4 SAS AF: 0.000415 AC: 0.000415282 AN: 0.000415282

Gnomad4 FIN AF: 0.000189 AC: 0.000189358 AN: 0.000189358

Gnomad4 NFE AF: 0.000779 AC: 0.000779481 AN: 0.000779481

Gnomad4 OTH AF: 0.000474 AC: 0.000474383 AN: 0.000474383

Alfa AF: 0.000623 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:9 Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypomyelinating leukodystrophy 9 Pathogenic:7

Aug 20, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Mar 22, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 15, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2 Uncertain:1 Benign:1

Mar 08, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_moderate -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Dec 10, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

Oct 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RARS1 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 0.00043 in 1607570 control chromosomes in the gnomAD database, including 2 homozygotes. The presence of two homozygotes for a disorder with onset in the first year of life, supports a benign outcome. c.1367C>T has been reported in the literature in the presumed compound heterozygous state in at-least 2 individuals affected with clinical features of Hypomyelinating Leukodystrophy 9 (example, Nafisinia_2017, Mendes_2020). At-least one of these cases involved a second variant that presumably escapes nonsense mediated decay (NMD) and its parent of origin (de-novo versus paternal) was not clearly established (Nafisina_2017). At least one publication reports experimental evidence evaluating an impact on protein function. This variant appeared to negatively impact protein localization/folding and the most pronounced variant effect results in >50%-90% of normal enzymatic activity in vitro (example, Li_2021, Matsumoto_2019), however cell background and some assay designs were not clearly relevant to the tissues involved in RARS1-related conditions. The following publications have been ascertained in the context of this evaluation (PMID: 33515434, 31737794, 31814314, 28905880). ClinVar contains an entry for this variant (Variation ID: 265854). Based on the evidence outlined above, the variant was classified as likely benign. -

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
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
Mutation Taster		=19/81	disease causing (ClinVar)

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;