1-214657274-A-G

Variant names:

• chr1-214657274-A-G
• rs438034
• NM_016343.4:c.8827A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016343.4(CENPF):​c.8827A>G​(p.Arg2943Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 1,613,690 control chromosomes in the GnomAD database, including 255,407 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21689 hom., cov: 32)
  • Exomes 𝑓: 0.56 (233718 hom.)
• Consequence: CENPF NM_016343.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.952
• Publications: 47 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.1669925E-7).
• BP6: Variant 1-214657274-A-G is Benign according to our data. Variant chr1-214657274-A-G is described in CliVar as Benign. Clinvar id is 1209683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-214657274-A-G is described in CliVar as Benign. Clinvar id is 1209683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-214657274-A-G is described in CliVar as Benign. Clinvar id is 1209683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-214657274-A-G is described in CliVar as Benign. Clinvar id is 1209683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-214657274-A-G is described in CliVar as Benign. Clinvar id is 1209683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-214657274-A-G is described in CliVar as Benign. Clinvar id is 1209683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPF	NM_016343.4	c.8827A>G	p.Arg2943Gly	missense_variant	Exon 18 of 20	ENST00000366955.8	NP_057427.3
CENPF	XM_017000086.3	c.8827A>G	p.Arg2943Gly	missense_variant	Exon 18 of 20		XP_016855575.1
CENPF	XM_011509082.4	c.8650A>G	p.Arg2884Gly	missense_variant	Exon 17 of 19		XP_011507384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPF	ENST00000366955.8	c.8827A>G	p.Arg2943Gly	missense_variant	Exon 18 of 20	1	NM_016343.4	ENSP00000355922.3
CENPF	ENST00000706765.1	c.8650A>G	p.Arg2884Gly	missense_variant	Exon 17 of 19			ENSP00000516538.1
CENPF	ENST00000469862.1	n.598A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
CENPF	ENST00000706766.1	n.926A>G		non_coding_transcript_exon_variant	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79601 AN: 151862 Hom.: 21675 Cov.: 32

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.877

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.558

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.550

GnomAD2 exomes AF: 0.606 AC: 151878 AN: 250824 AF XY: 0.605

Gnomad AFR exome AF: 0.385

Gnomad AMR exome AF: 0.723

Gnomad ASJ exome AF: 0.557

Gnomad EAS exome AF: 0.884

Gnomad FIN exome AF: 0.572

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.588

GnomAD4 exome AF: 0.559 AC: 816928 AN: 1461710 Hom.: 233718 Cov.: 53 AF XY: 0.562 AC XY: 408903 AN XY: 727156

African (AFR) AF: 0.378 AC: 12647 AN: 33474

American (AMR) AF: 0.712 AC: 31845 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 14367 AN: 26132

East Asian (EAS) AF: 0.879 AC: 34902 AN: 39694

South Asian (SAS) AF: 0.704 AC: 60737 AN: 86252

European-Finnish (FIN) AF: 0.574 AC: 30668 AN: 53398

Middle Eastern (MID) AF: 0.610 AC: 3518 AN: 5768

European-Non Finnish (NFE) AF: 0.534 AC: 594299 AN: 1111878

Other (OTH) AF: 0.562 AC: 33945 AN: 60394

GnomAD4 genome AF: 0.524 AC: 79647 AN: 151980 Hom.: 21689 Cov.: 32 AF XY: 0.531 AC XY: 39418 AN XY: 74290

African (AFR) AF: 0.391 AC: 16223 AN: 41454

American (AMR) AF: 0.636 AC: 9711 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1889 AN: 3466

East Asian (EAS) AF: 0.878 AC: 4523 AN: 5154

South Asian (SAS) AF: 0.716 AC: 3447 AN: 4814

European-Finnish (FIN) AF: 0.572 AC: 6046 AN: 10568

Middle Eastern (MID) AF: 0.559 AC: 162 AN: 290

European-Non Finnish (NFE) AF: 0.531 AC: 36105 AN: 67952

Other (OTH) AF: 0.552 AC: 1160 AN: 2102

Alfa AF: 0.537 Hom.: 85613

Bravo AF: 0.523

TwinsUK AF: 0.544 AC: 2018

ALSPAC AF: 0.539 AC: 2078

ESP6500AA AF: 0.397 AC: 1750

ESP6500EA AF: 0.541 AC: 4649

ExAC AF: 0.598 AC: 72611

Asia WGS AF: 0.777 AC: 2699 AN: 3478

EpiCase AF: 0.534

EpiControl AF: 0.545

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stromme syndrome Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.4
DANN	Benign	0.68
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	6.2e-7	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.95
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.96	N
REVEL	Benign	0.033
Sift	Benign	0.66	T
Sift4G	Benign	0.25	T
Vest4		0.036
MPC		0.064
ClinPred		0.0058	T
GERP RS		2.5
Varity_R		0.036
gMVP		0.092
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs438034; hg19: chr1-214830617; COSMIC: COSV107455286; COSMIC: COSV107455286;