1-173807488-G-T

Variant names:

• chr1-173807488-G-T
• rs748581087
• NM_001387287.1:c.199C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001387287.1(CENPL):​c.199C>A​(p.Leu67Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000731 in 1,368,804 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L67F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CENPL NM_001387287.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPL	NM_001387287.1	c.199C>A	p.Leu67Ile	missense_variant	Exon 4 of 6	ENST00000682279.1	NP_001374216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPL	ENST00000682279.1	c.199C>A	p.Leu67Ile	missense_variant	Exon 4 of 6		NM_001387287.1	ENSP00000507473.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1368804 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 676736

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31286

American (AMR) AF: 0.00 AC: 0 AN: 36440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23132

East Asian (EAS) AF: 0.00 AC: 0 AN: 38576

South Asian (SAS) AF: 0.00 AC: 0 AN: 68854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5356

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060144

Other (OTH) AF: 0.00 AC: 0 AN: 55722

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;.;T
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.6	M;M;M
PhyloP100		1.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0090	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.38
MutPred		0.70		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.47
MPC		0.57
ClinPred		0.86	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.41
Mutation Taster		=70/30	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: rs748581087; hg19: chr1-173776626;