ENST00000649689:c.-147A>G

Variant names:

• chr1-173825083-A-G
• rs866230478
• ENST00000649689:c.-147A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000649689(DARS2):​c.-147A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000927 in 1,176,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: DARS2 ENST00000649689 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38

Genes affected

DARS2 (HGNC:25538): (aspartyl-tRNA synthetase 2, mitochondrial) The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. It is a mitochondrial enzyme that specifically aminoacylates aspartyl-tRNA. Mutations in this gene are associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). [provided by RefSeq, Nov 2009]

CENPL (HGNC:17879): (centromere protein L) CENPL is a subunit of a CENPH (MIM 605607)-CENPI (MIM 300065)-associated centromeric complex that targets CENPA (MIM 117139) to centromeres and is required for proper kinetochore function and mitotic progression (Okada et al., 2006) [PubMed 16622420].[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS2	NM_018122.5	c.-147A>G		5_prime_UTR_variant	Exon 1 of 17	ENST00000649689.2	NP_060592.2
CENPL	NM_001387287.1	c.-973T>C		upstream_gene_variant		ENST00000682279.1	NP_001374216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689	c.-147A>G		5_prime_UTR_variant	Exon 1 of 17		NM_018122.5	ENSP00000497569.1
CENPL	ENST00000682279.1	c.-973T>C		upstream_gene_variant			NM_001387287.1	ENSP00000507473.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.0000547 AC: 56 AN: 1023738 Hom.: 0 Cov.: 12 AF XY: 0.0000533 AC XY: 28 AN XY: 525376

Gnomad4 AFR exome AF: 0.00133

Gnomad4 AMR exome AF: 0.000173

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000593

Gnomad4 SAS exome AF: 0.0000133

Gnomad4 FIN exome AF: 0.0000239

Gnomad4 NFE exome AF: 0.00000946

Gnomad4 OTH exome AF: 0.000136

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74474

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000434

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.68

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: rs866230478; hg19: chr1-173794221;