NM_016343.4:c.8186G>T

Variant names:

• chr1-214652853-G-T
• rs335524
• NM_016343.4:c.8186G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016343.4(CENPF):​c.8186G>T​(p.Arg2729Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2729Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CENPF NM_016343.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0270
• Publications: 42 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07022548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPF	NM_016343.4	c.8186G>T	p.Arg2729Leu	missense_variant	Exon 16 of 20	ENST00000366955.8	NP_057427.3
CENPF	XM_017000086.3	c.8186G>T	p.Arg2729Leu	missense_variant	Exon 16 of 20		XP_016855575.1
CENPF	XM_011509082.4	c.8009G>T	p.Arg2670Leu	missense_variant	Exon 15 of 19		XP_011507384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPF	ENST00000366955.8	c.8186G>T	p.Arg2729Leu	missense_variant	Exon 16 of 20	1	NM_016343.4	ENSP00000355922.3
CENPF	ENST00000706765.1	c.8009G>T	p.Arg2670Leu	missense_variant	Exon 15 of 19			ENSP00000516538.1
CENPF	ENST00000467765.1	n.356G>T		non_coding_transcript_exon_variant	Exon 3 of 4	2
CENPF	ENST00000706766.1	n.285G>T		non_coding_transcript_exon_variant	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1444300 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 718014

African (AFR) AF: 0.00 AC: 0 AN: 32064

American (AMR) AF: 0.00 AC: 0 AN: 39950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25264

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.00 AC: 0 AN: 82020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107060

Other (OTH) AF: 0.00 AC: 0 AN: 59602

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.39
DANN	Benign	0.92
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.027
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.088
Sift	Uncertain	0.026	D;.
Sift4G	Benign	0.11	T;T
Vest4		0.25
MVP		0.061
MPC		0.098
ClinPred		0.13	T
GERP RS		-6.4
Varity_R		0.063
gMVP		0.028
Mutation Taster		=95/5	polymorphism

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: rs335524; hg19: chr1-214826196;