Genetic Variant NM_016343.4:c.8186G>C (chr1-214652853-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016343.4(CENPF):c.8186G>C(p.Arg2729Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. R2729Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

CENPF
NM_016343.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0270

Publications

42 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.111685365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPF	NM_016343.4 link	c.8186G>C	p.Arg2729Pro	missense_variant	Exon 16 of 20	ENST00000366955.8	NP_057427.3	P49454
CENPF	XM_017000086.3 link	c.8186G>C	p.Arg2729Pro	missense_variant	Exon 16 of 20		XP_016855575.1	P49454
CENPF	XM_011509082.4 link	c.8009G>C	p.Arg2670Pro	missense_variant	Exon 15 of 19		XP_011507384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CENPF	ENST00000366955.8 link	c.8186G>C	p.Arg2729Pro	missense_variant	Exon 16 of 20	1	NM_016343.4	ENSP00000355922.3	P49454
CENPF	ENST00000706765.1 link	c.8009G>C	p.Arg2670Pro	missense_variant	Exon 15 of 19			ENSP00000516538.1	A0A9L9PXU7
CENPF	ENST00000467765.1 link	n.356G>C		non_coding_transcript_exon_variant	Exon 3 of 4	2
CENPF	ENST00000706766.1 link	n.285G>C		non_coding_transcript_exon_variant	Exon 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151712

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74064

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41234

American (AMR)

AF:

0.00

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67926

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

50973

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

1.3

(source)

DANN

Benign

0.93

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

PhyloP100

-0.027

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.19

Sift

Uncertain

0.020

D;.

Sift4G

Benign

0.087

T;T

Vest4

0.32

MVP

0.081

MPC

0.24

ClinPred

0.56

GERP RS

-6.4

Varity_R

0.27

gMVP

0.16

Mutation Taster

=82/18

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over