1-214640439-A-G

Position:

• chr1-214640439-A-G

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.2101A>G​(p.Met701Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0629 in 1,614,010 control chromosomes in the GnomAD database, including 4,158 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M701L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.072 (462 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3696 hom.)
• Consequence: CENPF NM_016343.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.70

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=0.0017424524).
• BP6: Variant 1-214640439-A-G is Benign according to our data. Variant chr1-214640439-A-G is described in ClinVar as [Benign]. Clinvar id is 1209810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPF	NM_016343.4	c.2101A>G	p.Met701Val	missense_variant	12/20	ENST00000366955.8	NP_057427.3
CENPF	XM_017000086.3	c.2101A>G	p.Met701Val	missense_variant	12/20		XP_016855575.1
CENPF	XM_011509082.4	c.2101A>G	p.Met701Val	missense_variant	12/19		XP_011507384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPF	ENST00000366955.8	c.2101A>G	p.Met701Val	missense_variant	12/20	1	NM_016343.4	ENSP00000355922.3
CENPF	ENST00000706765.1	c.2101A>G	p.Met701Val	missense_variant	12/19			ENSP00000516538.1

Frequencies

GnomAD3 genomes AF: 0.0714 AC: 10861 AN: 152186 Hom.: 460 Cov.: 33

Gnomad AFR AF: 0.0951

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0500

Gnomad OTH AF: 0.0688

GnomAD3 exomes AF: 0.0831 AC: 20806 AN: 250402 Hom.: 1213 AF XY: 0.0817 AC XY: 11064 AN XY: 135350

Gnomad AFR exome AF: 0.0981

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.0541

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.146

Gnomad FIN exome AF: 0.0252

Gnomad NFE exome AF: 0.0488

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0621 AC: 90704 AN: 1461706 Hom.: 3696 Cov.: 34 AF XY: 0.0638 AC XY: 46411 AN XY: 727132

Gnomad4 AFR exome AF: 0.0976

Gnomad4 AMR exome AF: 0.148

Gnomad4 ASJ exome AF: 0.0517

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.145

Gnomad4 FIN exome AF: 0.0267

Gnomad4 NFE exome AF: 0.0505

Gnomad4 OTH exome AF: 0.0662

GnomAD4 genome AF: 0.0715 AC: 10894 AN: 152304 Hom.: 462 Cov.: 33 AF XY: 0.0724 AC XY: 5394 AN XY: 74480

Gnomad4 AFR AF: 0.0954

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.0522

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.0218

Gnomad4 NFE AF: 0.0500

Gnomad4 OTH AF: 0.0699

Alfa AF: 0.0552 Hom.: 515

Bravo AF: 0.0803

TwinsUK AF: 0.0574 AC: 213

ALSPAC AF: 0.0501 AC: 193

ESP6500AA AF: 0.0903 AC: 398

ESP6500EA AF: 0.0542 AC: 466

ExAC AF: 0.0819 AC: 9949

EpiCase AF: 0.0505

EpiControl AF: 0.0519

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	0.053
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.2
DANN	Benign	0.38
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.054	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.90	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.074
Sift	Benign	0.30	T
Sift4G	Benign	0.30	T
Polyphen		0.019	B
Vest4		0.0070
MPC		0.053
ClinPred		0.0030	T
GERP RS		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.064

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: rs3795524; hg19: chr1-214813782; COSMIC: COSV65277629;