rs1064792894

Variant names:

• chr5-168518034-CTA-C
• rs1064792894
• NM_002887.4:c.1846_1847delTA

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_002887.4(RARS1):​c.1846_1847delTA​(p.Tyr616LeufsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: RARS1 NM_002887.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.88
• Publications: 1 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: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0691 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-168518034-CTA-C is Pathogenic according to our data. Variant chr5-168518034-CTA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 424864.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS1	NM_002887.4	MANE Select	c.1846_1847delTA	p.Tyr616LeufsTer6	frameshift	Exon 14 of 15	NP_002878.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARS1	ENST00000231572.8	TSL:1 MANE Select	c.1846_1847delTA	p.Tyr616LeufsTer6	frameshift	Exon 14 of 15	ENSP00000231572.3
	RARS1	ENST00000520013.5	TSL:2	n.*1347_*1348delTA		non_coding_transcript_exon	Exon 13 of 14	ENSP00000429030.1
	RARS1	ENST00000520013.5	TSL:2	n.*1347_*1348delTA		3_prime_UTR	Exon 13 of 14	ENSP00000429030.1

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	Hypomyelinating leukodystrophy 9 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1064792894; hg19: chr5-167945039;