rs335524

chr1-214652853-G-Achr1-214652853-G-Cchr1-214652853-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016343.4(CENPF):c.8186G>A(p.Arg2729Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,593,726 control chromosomes in the GnomAD database, including 171,079 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15480 hom., cov: 32)
  • Exomes 𝑓: 0.45 (155599 hom.)
• Consequence: CENPF NM_016343.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0270

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=6.06294E-7).
• BP6: Variant 1-214652853-G-A is Benign according to our data. Variant chr1-214652853-G-A is described in ClinVar as [Benign]. Clinvar id is 1209682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPF	NM_016343.4	c.8186G>A	p.Arg2729Gln	missense_variant	16/20	ENST00000366955.8
CENPF	XM_017000086.3	c.8186G>A	p.Arg2729Gln	missense_variant	16/20
CENPF	XM_011509082.4	c.8009G>A	p.Arg2670Gln	missense_variant	15/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPF	ENST00000366955.8	c.8186G>A	p.Arg2729Gln	missense_variant	16/20	1	NM_016343.4	P2
CENPF	ENST00000706765.1	c.8009G>A	p.Arg2670Gln	missense_variant	15/19			A2
CENPF	ENST00000467765.1	n.356G>A		non_coding_transcript_exon_variant	3/4	2
CENPF	ENST00000706766.1	n.285G>A		non_coding_transcript_exon_variant	1/5

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66150 AN: 151652 Hom.: 15473 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.878

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.469

GnomAD3 exomes AF: 0.519 AC: 121624 AN: 234268 Hom.: 34391 AF XY: 0.517 AC XY: 65453 AN XY: 126482

Gnomad AFR exome AF: 0.308

Gnomad AMR exome AF: 0.681

Gnomad ASJ exome AF: 0.472

Gnomad EAS exome AF: 0.887

Gnomad SAS exome AF: 0.639

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.428

Gnomad OTH exome AF: 0.505

GnomAD4 exome AF: 0.452 AC: 651614 AN: 1441958 Hom.: 155599 Cov.: 33 AF XY: 0.457 AC XY: 327290 AN XY: 716946

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.663

Gnomad4 ASJ exome AF: 0.467

Gnomad4 EAS exome AF: 0.883

Gnomad4 SAS exome AF: 0.634

Gnomad4 FIN exome AF: 0.492

Gnomad4 NFE exome AF: 0.416

Gnomad4 OTH exome AF: 0.467

GnomAD4 genome AF: 0.436 AC: 66182 AN: 151768 Hom.: 15480 Cov.: 32 AF XY: 0.447 AC XY: 33159 AN XY: 74152

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.579

Gnomad4 ASJ AF: 0.459

Gnomad4 EAS AF: 0.879

Gnomad4 SAS AF: 0.652

Gnomad4 FIN AF: 0.491

Gnomad4 NFE AF: 0.419

Gnomad4 OTH AF: 0.472

Alfa AF: 0.437 Hom.: 36242

Bravo AF: 0.438

TwinsUK AF: 0.419 AC: 1554

ALSPAC AF: 0.416 AC: 1605

ESP6500AA AF: 0.318 AC: 1400

ESP6500EA AF: 0.429 AC: 3691

ExAC AF: 0.515 AC: 62482

Asia WGS AF: 0.747 AC: 2590 AN: 3478

EpiCase AF: 0.429

EpiControl AF: 0.439

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -

Stromme syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.0070
Dann	Benign	0.13
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	6.1e-7	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.66	N;.
REVEL	Benign	0.054
Sift	Benign	0.69	T;.
Sift4G	Benign	0.66	T;T
Vest4		0.030
MPC		0.060
ClinPred		0.000022	T
GERP RS		-6.4
Varity_R		0.017
gMVP		0.0069

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: rs335524; hg19: chr1-214826196;