rs866230478

Variant names:

• chr1-173825083-A-G
• rs866230478
• NM_018122.5:c.-147A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018122.5(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 NM_018122.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018122.5. 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
	DARS2	NM_018122.5	MANE Select	c.-147A>G		5_prime_UTR	Exon 1 of 17	NP_060592.2
	DARS2	NM_001365212.1		c.-147A>G		5_prime_UTR	Exon 1 of 16	NP_001352141.1	A0A3B3IT01
	DARS2	NM_001365213.2		c.-147A>G		5_prime_UTR	Exon 1 of 14	NP_001352142.1	A0A3B3ITS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS2	ENST00000649689.2	MANE Select	c.-147A>G		5_prime_UTR	Exon 1 of 17	ENSP00000497569.1	Q6PI48
	DARS2	ENST00000647645.1		c.-147A>G		5_prime_UTR	Exon 1 of 16	ENSP00000497450.1	A0A3B3ISK7
	DARS2	ENST00000893356.1		c.-147A>G		5_prime_UTR	Exon 1 of 16	ENSP00000563415.1

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

African (AFR) AF: 0.00133 AC: 32 AN: 24118

American (AMR) AF: 0.000173 AC: 7 AN: 40426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21012

East Asian (EAS) AF: 0.0000593 AC: 2 AN: 33710

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 74930

European-Finnish (FIN) AF: 0.0000239 AC: 1 AN: 41814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3718

European-Non Finnish (NFE) AF: 0.00000946 AC: 7 AN: 740014

Other (OTH) AF: 0.000136 AC: 6 AN: 43996

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

African (AFR) AF: 0.00115 AC: 48 AN: 41566

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000434

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.68
PhyloP100		1.4
PromoterAI		0.017	Neutral
Mutation Taster		=300/0	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: rs866230478; hg19: chr1-173794221;