dbSNP rs200976140: CENPF:p.Glu912* (chr1-214641072-G-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_016343.4(CENPF):c.2734G>T(p.Glu912*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 1,413,580 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 (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CENPF
NM_016343.4 stop_gained

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.935

Publications

0 publications found

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]

CENPF Gene-Disease associations (from GenCC):

Stromme syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Illumina, Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

CENPF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-214641072-G-T is Pathogenic according to our data. Variant chr1-214641072-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 224500.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPF	NM_016343.4 link	c.2734G>T	p.Glu912*	stop_gained	Exon 12 of 20	ENST00000366955.8	NP_057427.3	P49454
CENPF	XM_017000086.3 link	c.2734G>T	p.Glu912*	stop_gained	Exon 12 of 20		XP_016855575.1	P49454
CENPF	XM_011509082.4 link	c.2734G>T	p.Glu912*	stop_gained	Exon 12 of 19		XP_011507384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPF	ENST00000366955.8 link	c.2734G>T	p.Glu912*	stop_gained	Exon 12 of 20	1	NM_016343.4	ENSP00000355922.3		P49454
CENPF	ENST00000706765.1 link	c.2734G>T	p.Glu912*	stop_gained	Exon 12 of 19			ENSP00000516538.1		A0A9L9PXU7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000486

AC:

AN:

205648

AF XY:

0.0000449

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000100

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000177

AC:

AN:

1413580

Hom.:

Cov.:

AF XY:

0.0000128

AC XY:

AN XY:

701530

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30792

American (AMR)

AF:

0.00

AC:

AN:

30864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22898

East Asian (EAS)

AF:

0.00

AC:

AN:

39470

South Asian (SAS)

AF:

0.00

AC:

AN:

77074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5508

European-Non Finnish (NFE)

AF:

0.0000219

AC:

AN:

1097170

Other (OTH)

AF:

0.0000172

AC:

AN:

58204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000352

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Stromme syndrome

Pathogenic:1

Feb 19, 2025

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Benign

0.56

PhyloP100

0.94

Vest4

0.82

GERP RS

4.5

Mutation Taster

=6/194

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over