rs62000407

chr1-214642149-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_016343.4(CENPF):c.3811A>G(p.Lys1271Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,614,068 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (4 hom.)
• Consequence: CENPF NM_016343.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.38

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006287843).
• BP6: Variant 1-214642149-A-G is Benign according to our data. Variant chr1-214642149-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434706.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00233 (355/152350) while in subpopulation NFE AF= 0.00392 (267/68032). AF 95% confidence interval is 0.00354. There are 1 homozygotes in gnomad4. There are 159 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPF	NM_016343.4	c.3811A>G	p.Lys1271Glu	missense_variant	12/20	ENST00000366955.8
CENPF	XM_017000086.3	c.3811A>G	p.Lys1271Glu	missense_variant	12/20
CENPF	XM_011509082.4	c.3811A>G	p.Lys1271Glu	missense_variant	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPF	ENST00000366955.8	c.3811A>G	p.Lys1271Glu	missense_variant	12/20	1	NM_016343.4	P2
CENPF	ENST00000706765.1	c.3811A>G	p.Lys1271Glu	missense_variant	12/19			A2

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00239 AC: 599 AN: 250488 Hom.: 0 AF XY: 0.00265 AC XY: 359 AN XY: 135358

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00128

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00411

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00305 AC: 4457 AN: 1461718 Hom.: 4 Cov.: 35 AF XY: 0.00303 AC XY: 2204 AN XY: 727140

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.000974

Gnomad4 NFE exome AF: 0.00360

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.00213 AC XY: 159 AN XY: 74502

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00392

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00367 Hom.: 2

Bravo AF: 0.00222

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00272 AC: 330

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CENPF: BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Nov 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 31, 2017

- -

CENPF-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.079
Sift	Benign	0.036	D
Sift4G	Benign	0.41	T
Polyphen		0.98	D
Vest4		0.20
MVP		0.27
MPC		0.077
ClinPred		0.020	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs62000407; hg19: chr1-214815492; COSMIC: COSV99055844;