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rs786205697

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_016343.4(CENPF):​c.8692C>T​(p.Arg2898Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CENPF
NM_016343.4 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.766
Variant links:
Genes affected
CENPF (HGNC:1857): (centromere protein F) This gene encodes a protein that associates with the centromere-kinetochore complex. The protein is a component of the nuclear matrix during the G2 phase of interphase. In late G2 the protein associates with the kinetochore and maintains this association through early anaphase. It localizes to the spindle midzone and the intracellular bridge in late anaphase and telophase, respectively, and is thought to be subsequently degraded. The localization of this protein suggests that it may play a role in chromosome segregation during mitotis. It is thought to form either a homodimer or heterodimer. Autoantibodies against this protein have been found in patients with cancer or graft versus host disease. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-214657139-C-T is Pathogenic according to our data. Variant chr1-214657139-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 190387.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-214657139-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CENPFNM_016343.4 linkuse as main transcriptc.8692C>T p.Arg2898Ter stop_gained 18/20 ENST00000366955.8
CENPFXM_017000086.3 linkuse as main transcriptc.8692C>T p.Arg2898Ter stop_gained 18/20
CENPFXM_011509082.4 linkuse as main transcriptc.8515C>T p.Arg2839Ter stop_gained 17/19

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CENPFENST00000366955.8 linkuse as main transcriptc.8692C>T p.Arg2898Ter stop_gained 18/201 NM_016343.4 P2
CENPFENST00000706765.1 linkuse as main transcriptc.8515C>T p.Arg2839Ter stop_gained 17/19 A2
CENPFENST00000469862.1 linkuse as main transcriptn.463C>T non_coding_transcript_exon_variant 2/22
CENPFENST00000706766.1 linkuse as main transcriptn.791C>T non_coding_transcript_exon_variant 3/5

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461858
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
Alfa
AF:
0.0000611
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Stromme syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 20, 2022- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
36
DANN
Uncertain
0.98
Eigen
Benign
0.047
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.24
N
MutationTaster
Benign
1.0
A
Vest4
0.19
GERP RS
2.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs786205697; hg19: chr1-214830482; COSMIC: COSV65279210; COSMIC: COSV65279210; API