rs144034954

chr1-214640736-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016343.4(CENPF):c.2398A>G(p.Ile800Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000443 in 1,614,122 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (4 hom.)
• Consequence: CENPF NM_016343.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0250

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027014613).
• BP6: Variant 1-214640736-A-G is Benign according to our data. Variant chr1-214640736-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 434711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00177 (269/152332) while in subpopulation AFR AF= 0.00544 (226/41574). AF 95% confidence interval is 0.00486. There are 3 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPF	NM_016343.4	c.2398A>G	p.Ile800Val	missense_variant	12/20	ENST00000366955.8
CENPF	XM_017000086.3	c.2398A>G	p.Ile800Val	missense_variant	12/20
CENPF	XM_011509082.4	c.2398A>G	p.Ile800Val	missense_variant	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPF	ENST00000366955.8	c.2398A>G	p.Ile800Val	missense_variant	12/20	1	NM_016343.4	P2
CENPF	ENST00000706765.1	c.2398A>G	p.Ile800Val	missense_variant	12/19			A2

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152214 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00538

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000693 AC: 173 AN: 249742 Hom.: 0 AF XY: 0.000510 AC XY: 69 AN XY: 135406

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00507

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000305 AC: 446 AN: 1461790 Hom.: 4 Cov.: 34 AF XY: 0.000279 AC XY: 203 AN XY: 727182

Gnomad4 AFR exome AF: 0.00579

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.00497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152332 Hom.: 3 Cov.: 33 AF XY: 0.00185 AC XY: 138 AN XY: 74492

Gnomad4 AFR AF: 0.00544

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000611 Hom.: 0

Bravo AF: 0.00201

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00640 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000791 AC: 96

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CENPF: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Mar 31, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 01, 2018

- -

CENPF-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 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	0.068
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.68
Dann	Benign	0.28
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.021
Sift	Benign	0.89	T
Sift4G	Benign	1.0	T
Polyphen		0.025	B
Vest4		0.042
MVP		0.16
MPC		0.047
ClinPred		0.0017	T
GERP RS		0.13
Varity_R		0.013
gMVP		0.014

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: rs144034954; hg19: chr1-214814079;