chr1-214646756-A-G

Position:

• chr1-214646756-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016343.4(CENPF):​c.7186A>G​(p.Asn2396Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,612,922 control chromosomes in the GnomAD database, including 185,145 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (12355 hom., cov: 33)
  • Exomes 𝑓: 0.47 (172790 hom.)
• Consequence: CENPF NM_016343.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.224

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=2.8148293E-4).
• BP6: Variant 1-214646756-A-G is Benign according to our data. Variant chr1-214646756-A-G is described in ClinVar as [Benign]. Clinvar id is 1209678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPF	NM_016343.4	c.7186A>G	p.Asn2396Asp	missense_variant	13/20	ENST00000366955.8	NP_057427.3
CENPF	XM_017000086.3	c.7186A>G	p.Asn2396Asp	missense_variant	13/20		XP_016855575.1
CENPF	XM_011509082.4	c.7186A>G	p.Asn2396Asp	missense_variant	13/19		XP_011507384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPF	ENST00000366955.8	c.7186A>G	p.Asn2396Asp	missense_variant	13/20	1	NM_016343.4	ENSP00000355922	P2
CENPF	ENST00000706765.1	c.7186A>G	p.Asn2396Asp	missense_variant	13/19			ENSP00000516538	A2

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54767 AN: 152054 Hom.: 12356 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.380

GnomAD3 exomes AF: 0.391 AC: 97511 AN: 249190 Hom.: 21960 AF XY: 0.402 AC XY: 54353 AN XY: 135080

Gnomad AFR exome AF: 0.0980

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.494

Gnomad EAS exome AF: 0.117

Gnomad SAS exome AF: 0.324

Gnomad FIN exome AF: 0.452

Gnomad NFE exome AF: 0.512

Gnomad OTH exome AF: 0.428

GnomAD4 exome AF: 0.474 AC: 691912 AN: 1460750 Hom.: 172790 Cov.: 39 AF XY: 0.472 AC XY: 342742 AN XY: 726696

Gnomad4 AFR exome AF: 0.0904

Gnomad4 AMR exome AF: 0.268

Gnomad4 ASJ exome AF: 0.493

Gnomad4 EAS exome AF: 0.134

Gnomad4 SAS exome AF: 0.326

Gnomad4 FIN exome AF: 0.448

Gnomad4 NFE exome AF: 0.520

Gnomad4 OTH exome AF: 0.443

GnomAD4 genome AF: 0.360 AC: 54768 AN: 152172 Hom.: 12355 Cov.: 33 AF XY: 0.355 AC XY: 26404 AN XY: 74400

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.497

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.312

Gnomad4 FIN AF: 0.446

Gnomad4 NFE AF: 0.519

Gnomad4 OTH AF: 0.379

Alfa AF: 0.477 Hom.: 46547

Bravo AF: 0.339

TwinsUK AF: 0.504 AC: 1870

ALSPAC AF: 0.521 AC: 2007

ESP6500AA AF: 0.118 AC: 521

ESP6500EA AF: 0.509 AC: 4376

ExAC AF: 0.390 AC: 47300

Asia WGS AF: 0.201 AC: 704 AN: 3478

EpiCase AF: 0.512

EpiControl AF: 0.507

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -

Stromme syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.5
DANN	Benign	0.77
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.00028	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.91	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.14
Sift	Benign	0.55	T
Sift4G	Benign	0.70	T
Vest4		0.026
MPC		0.059
ClinPred		0.012	T
GERP RS		4.0
Varity_R		0.055
gMVP		0.045

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: rs3748697; hg19: chr1-214820099; COSMIC: COSV65272888; COSMIC: COSV65272888;