chr5-168486527-C-T

Variant names:

• chr5-168486527-C-T
• rs1341221155
• NM_002887.4:c.29C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002887.4(RARS1):​c.29C>T​(p.Ala10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000962 in 1,558,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RARS1 NM_002887.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49
• Publications: 0 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: AR, Unknown Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27125013).

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.29C>T	p.Ala10Val	missense	Exon 1 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.29C>T	p.Ala10Val	missense	Exon 1 of 15	ENSP00000231572.3	P54136-1
	RARS1	ENST00000922755.1		c.29C>T	p.Ala10Val	missense	Exon 1 of 15	ENSP00000592814.1
	RARS1	ENST00000953515.1		c.29C>T	p.Ala10Val	missense	Exon 1 of 16	ENSP00000623574.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000121 AC: 2 AN: 165600 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000303

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000995 AC: 14 AN: 1406552 Hom.: 0 Cov.: 35 AF XY: 0.0000101 AC XY: 7 AN XY: 694224

African (AFR) AF: 0.00 AC: 0 AN: 32462

American (AMR) AF: 0.00 AC: 0 AN: 35894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25200

East Asian (EAS) AF: 0.00 AC: 0 AN: 37028

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1082474

Other (OTH) AF: 0.00 AC: 0 AN: 58352

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.5
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.27
Sift	Benign	0.096	T
Sift4G	Benign	0.28	T
Polyphen		0.26	B
Vest4		0.52
MVP		0.58
MPC		0.13
ClinPred		0.38	T
GERP RS		4.0
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.18
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs1341221155; hg19: chr5-167913532;