rs3795524

Positions:

• chr1-214640439-A-C
• chr1-214640439-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.2101A>C​(p.Met701Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000654 in 1,614,050 control chromosomes in the GnomAD database, including 7 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M701V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (4 hom.)
• Consequence: CENPF NM_016343.4 missense
• Clinical Significance: Benign/Likely 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=0.004922956).
• BP6: Variant 1-214640439-A-C is Benign according to our data. Variant chr1-214640439-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 775665.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 = 0.00332 (506/152314) while in subpopulation AFR AF= 0.0112 (467/41560). AF 95% confidence interval is 0.0104. There are 3 homozygotes in gnomad4. There are 251 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPF	NM_016343.4	c.2101A>C	p.Met701Leu	missense_variant	12/20	ENST00000366955.8	NP_057427.3
CENPF	XM_017000086.3	c.2101A>C	p.Met701Leu	missense_variant	12/20		XP_016855575.1
CENPF	XM_011509082.4	c.2101A>C	p.Met701Leu	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>C	p.Met701Leu	missense_variant	12/20	1	NM_016343.4	ENSP00000355922.3
CENPF	ENST00000706765.1	c.2101A>C	p.Met701Leu	missense_variant	12/19			ENSP00000516538.1

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 507 AN: 152196 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000927 AC: 232 AN: 250402 Hom.: 1 AF XY: 0.000680 AC XY: 92 AN XY: 135350

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000376 AC: 550 AN: 1461736 Hom.: 4 Cov.: 34 AF XY: 0.000329 AC XY: 239 AN XY: 727146

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00332 AC: 506 AN: 152314 Hom.: 3 Cov.: 33 AF XY: 0.00337 AC XY: 251 AN XY: 74482

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00284

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00110 AC: 133

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CENPF: BP4, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.5
DANN	Benign	0.39
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.067	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.90	T
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.069
Sift	Benign	0.31	T
Sift4G	Benign	0.32	T
Polyphen		0.019	B
Vest4		0.078
MutPred		0.18		Loss of methylation at K697 (P = 0.0528);
MVP		0.13
MPC		0.050
ClinPred		0.0029	T
GERP RS		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.042

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;