1-173824697-G-A

Variant names:

• chr1-173824697-G-A
• rs533128814
• NM_001387287.1:c.-587C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001387287.1(CENPL):​c.-587C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 165,198 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: CENPL NM_001387287.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.684
• Publications: 0 publications found

Genes affected

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]

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]

DARS2 Gene-Disease associations (from GenCC):

• leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387287.1. 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
	CENPL	NM_001387287.1	MANE Select	c.-587C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_001374216.1	Q8N0S6-1
	DARS2	NM_018122.5	MANE Select	c.-533G>A		5_prime_UTR	Exon 1 of 17	NP_060592.2
	CENPL	NM_001387287.1	MANE Select	c.-587C>T		5_prime_UTR	Exon 1 of 6	NP_001374216.1	Q8N0S6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPL	ENST00000682279.1	MANE Select	c.-587C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000507473.1	Q8N0S6-1
	DARS2	ENST00000649689.2	MANE Select	c.-533G>A		5_prime_UTR	Exon 1 of 17	ENSP00000497569.1	Q6PI48
	CENPL	ENST00000682279.1	MANE Select	c.-587C>T		5_prime_UTR	Exon 1 of 6	ENSP00000507473.1	Q8N0S6-1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152188 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00462

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

GnomAD4 exome AF: 0.000233 AC: 3 AN: 12892 Hom.: 0 Cov.: 0 AF XY: 0.000427 AC XY: 3 AN XY: 7026

African (AFR) AF: 0.00 AC: 0 AN: 198

American (AMR) AF: 0.00 AC: 0 AN: 1584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 132

East Asian (EAS) AF: 0.00521 AC: 3 AN: 576

South Asian (SAS) AF: 0.00 AC: 0 AN: 2584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 42

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 6816

Other (OTH) AF: 0.00 AC: 0 AN: 632

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152306 Hom.: 2 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74474

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15296

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

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

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	1.8
DANN	Benign	0.76
PhyloP100		-0.68
PromoterAI		-0.12	Neutral

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: rs533128814; hg19: chr1-173793835;