rs774269116

Variant names:

• chr1-214613801-C-G
• rs774269116
• NM_016343.4:c.47C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016343.4(CENPF):​c.47C>G​(p.Ala16Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CENPF NM_016343.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPF	NM_016343.4	c.47C>G	p.Ala16Gly	missense_variant	Exon 2 of 20	ENST00000366955.8	NP_057427.3
CENPF	XM_017000086.3	c.47C>G	p.Ala16Gly	missense_variant	Exon 2 of 20		XP_016855575.1
CENPF	XM_011509082.4	c.47C>G	p.Ala16Gly	missense_variant	Exon 2 of 19		XP_011507384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPF	ENST00000366955.8	c.47C>G	p.Ala16Gly	missense_variant	Exon 2 of 20	1	NM_016343.4	ENSP00000355922.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250350 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135342

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461014 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.47C>G (p.A16G) alteration is located in exon 2 (coding exon 1) of the CENPF gene. This alteration results from a C to G substitution at nucleotide position 47, causing the alanine (A) at amino acid position 16 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.80	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.80		Loss of stability (P = 0.1353);
MVP		0.41
MPC		0.35
ClinPred		0.92	D
GERP RS		5.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.39
gMVP		0.20

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: rs774269116; hg19: chr1-214787144;