rs139644798

Variant names:

• chr5-168510601-C-T
• rs139644798
• NM_002887.4:c.1367C>T
• RARS1 p.Ser456Leu

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PS3 BP4 BS1 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). ClinVar reports functional evidence for this variant: "SCV002557765: "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)."". 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:2 B:2
• Conservation: PhyloP100: 7.45
• Publications: 20 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002557765: "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)."
• 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 passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,Unknown gene

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.1367C>T	p.Ser456Leu	missense	Exon 12 of 15	NP_002878.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS1	ENST00000231572.8	TSL:1 MANE Select	c.1367C>T	p.Ser456Leu	missense	Exon 12 of 15	ENSP00000231572.3	P54136-1
	RARS1	ENST00000922755.1		c.1391C>T	p.Ser464Leu	missense	Exon 12 of 15	ENSP00000592814.1
	RARS1	ENST00000953515.1		c.1379C>T	p.Ser460Leu	missense	Exon 13 of 16	ENSP00000623574.1

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

African (AFR) AF: 0.000302 AC: 10 AN: 33064

American (AMR) AF: 0.0000937 AC: 4 AN: 42682

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.000177 AC: 15 AN: 84512

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53364

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5758

European-Non Finnish (NFE) AF: 0.000502 AC: 557 AN: 1110312

Other (OTH) 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

African (AFR) AF: 0.0000482 AC: 2 AN: 41518

American (AMR) AF: 0.000262 AC: 4 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 67994

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000623 Hom.: 1

Bravo AF: 0.000321

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
7	-	-	Hypomyelinating leukodystrophy 9 (7)
3	1	1	not provided (5)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs139644798;

hg19: chr5-167937606;

COSMIC: COSV51564187;

COSMIC: COSV51564187;