NM_016343.4:c.4355A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_016343.4(CENPF):c.4355A>G(p.Asn1452Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000524 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

CENPF
NM_016343.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.951

Publications

4 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021950841).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00054 (790/1461830) while in subpopulation NFE AF = 0.00067 (745/1111996). AF 95% confidence interval is 0.000629. There are 0 homozygotes in GnomAdExome4. There are 377 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPF	NM_016343.4 link	c.4355A>G	p.Asn1452Ser	missense_variant	Exon 12 of 20	ENST00000366955.8	NP_057427.3	P49454
CENPF	XM_017000086.3 link	c.4355A>G	p.Asn1452Ser	missense_variant	Exon 12 of 20		XP_016855575.1	P49454
CENPF	XM_011509082.4 link	c.4355A>G	p.Asn1452Ser	missense_variant	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.4355A>G	p.Asn1452Ser	missense_variant	Exon 12 of 20	1	NM_016343.4	ENSP00000355922.3		P49454
CENPF	ENST00000706765.1 link	c.4355A>G	p.Asn1452Ser	missense_variant	Exon 12 of 19			ENSP00000516538.1		A0A9L9PXU7

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000315

AC:

AN:

250920

AF XY:

0.000310

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000627

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000540

AC:

790

AN:

1461830

Hom.:

Cov.:

AF XY:

0.000518

AC XY:

377

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000281

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000670

AC:

745

AN:

1111996

Other (OTH)

AF:

0.000447

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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

AF:

0.000368

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41456

American (AMR)

AF:

0.0000655

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68042

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000506

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000395

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 10, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Stromme syndrome

Uncertain:1

May 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.87

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.013

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.71

M_CAP

Benign

0.0036

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.97

PhyloP100

0.95

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.030

REVEL

Benign

0.087

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.055

Vest4

0.066

MVP

0.27

MPC

0.045

ClinPred

0.020

GERP RS

0.79

Varity_R

0.016

gMVP

0.046

Mutation Taster

=97/3

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over