rs200976140

chr1-214641072-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_016343.4(CENPF):c.2734G>T(p.Glu912Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 1,413,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CENPF NM_016343.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.935

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-214641072-G-T is Pathogenic according to our data. Variant chr1-214641072-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 224500.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-214641072-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPF	NM_016343.4	c.2734G>T	p.Glu912Ter	stop_gained	12/20	ENST00000366955.8
CENPF	XM_017000086.3	c.2734G>T	p.Glu912Ter	stop_gained	12/20
CENPF	XM_011509082.4	c.2734G>T	p.Glu912Ter	stop_gained	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPF	ENST00000366955.8	c.2734G>T	p.Glu912Ter	stop_gained	12/20	1	NM_016343.4	P2
CENPF	ENST00000706765.1	c.2734G>T	p.Glu912Ter	stop_gained	12/19			A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000486 AC: 10 AN: 205648 Hom.: 0 AF XY: 0.0000449 AC XY: 5 AN XY: 111476

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000100

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000177 AC: 25 AN: 1413580 Hom.: 0 Cov.: 34 AF XY: 0.0000128 AC XY: 9 AN XY: 701530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000219

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000352 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Stromme syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 20, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.56	D
MutationTaster	Benign	1.0	A
Vest4		0.82
GERP RS		4.5

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: rs200976140; hg19: chr1-214814415;