rs62000407

Variant names:

• chr1-214642149-A-G
• rs62000407
• NM_016343.4:c.3811A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000366955.8(CENPF):​c.3811A>G​(p.Lys1271Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,614,068 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (4 hom.)
• Consequence: CENPF ENST00000366955.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.38
• Publications: 11 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006287843).
• BP6: Variant 1-214642149-A-G is Benign according to our data. Variant chr1-214642149-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434706.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00233 (355/152350) while in subpopulation NFE AF = 0.00392 (267/68032). AF 95% confidence interval is 0.00354. There are 1 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000366955.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPF	NM_016343.4	MANE Select	c.3811A>G	p.Lys1271Glu	missense	Exon 12 of 20	NP_057427.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPF	ENST00000366955.8	TSL:1 MANE Select	c.3811A>G	p.Lys1271Glu	missense	Exon 12 of 20	ENSP00000355922.3
	CENPF	ENST00000706765.1		c.3811A>G	p.Lys1271Glu	missense	Exon 12 of 19	ENSP00000516538.1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00239 AC: 599 AN: 250488 AF XY: 0.00265

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00411

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00305 AC: 4457 AN: 1461718 Hom.: 4 Cov.: 35 AF XY: 0.00303 AC XY: 2204 AN XY: 727140

African (AFR) AF: 0.000448 AC: 15 AN: 33476

American (AMR) AF: 0.00130 AC: 58 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.00144 AC: 124 AN: 86222

European-Finnish (FIN) AF: 0.000974 AC: 52 AN: 53398

Middle Eastern (MID) AF: 0.00832 AC: 48 AN: 5768

European-Non Finnish (NFE) AF: 0.00360 AC: 4000 AN: 1111960

Other (OTH) AF: 0.00219 AC: 132 AN: 60382

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.00213 AC XY: 159 AN XY: 74502

African (AFR) AF: 0.000794 AC: 33 AN: 41584

American (AMR) AF: 0.00157 AC: 24 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00392 AC: 267 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00346 Hom.: 2

Bravo AF: 0.00222

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00272 AC: 330

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00486

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	CENPF-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.079
Sift	Benign	0.036	D
Sift4G	Benign	0.41	T
Polyphen		0.98	D
Vest4		0.20
MVP		0.27
MPC		0.077
ClinPred		0.020	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.19
Mutation Taster		=91/9	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: rs62000407; hg19: chr1-214815492; COSMIC: COSV99055844;