chr1-214640439-A-G

Variant names:

• chr1-214640439-A-G
• rs3795524
• NM_016343.4:c.2101A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016343.4(CENPF):​c.2101A>G​(p.Met701Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0629 in 1,614,010 control chromosomes in the GnomAD database, including 4,158 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M701L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.072 (462 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3696 hom.)
• Consequence: CENPF NM_016343.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.70
• Publications: 22 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: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017424524).
• BP6: Variant 1-214640439-A-G is Benign according to our data. Variant chr1-214640439-A-G is described in ClinVar as Benign. ClinVar VariationId is 1209810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016343.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPF	NM_016343.4	MANE Select	c.2101A>G	p.Met701Val	missense	Exon 12 of 20	NP_057427.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPF	ENST00000366955.8	TSL:1 MANE Select	c.2101A>G	p.Met701Val	missense	Exon 12 of 20	ENSP00000355922.3	P49454
	CENPF	ENST00000934982.1		c.2221A>G	p.Met741Val	missense	Exon 13 of 21	ENSP00000605041.1
	CENPF	ENST00000934983.1		c.2101A>G	p.Met701Val	missense	Exon 12 of 20	ENSP00000605042.1

Frequencies

GnomAD3 genomes AF: 0.0714 AC: 10861 AN: 152186 Hom.: 460 Cov.: 33

Gnomad AFR AF: 0.0951

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0500

Gnomad OTH AF: 0.0688

GnomAD2 exomes AF: 0.0831 AC: 20806 AN: 250402 AF XY: 0.0817

Gnomad AFR exome AF: 0.0981

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.0541

Gnomad EAS exome AF: 0.134

Gnomad FIN exome AF: 0.0252

Gnomad NFE exome AF: 0.0488

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0621 AC: 90704 AN: 1461706 Hom.: 3696 Cov.: 34 AF XY: 0.0638 AC XY: 46411 AN XY: 727132

African (AFR) AF: 0.0976 AC: 3268 AN: 33476

American (AMR) AF: 0.148 AC: 6605 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0517 AC: 1351 AN: 26130

East Asian (EAS) AF: 0.124 AC: 4911 AN: 39684

South Asian (SAS) AF: 0.145 AC: 12539 AN: 86234

European-Finnish (FIN) AF: 0.0267 AC: 1428 AN: 53384

Middle Eastern (MID) AF: 0.0711 AC: 410 AN: 5766

European-Non Finnish (NFE) AF: 0.0505 AC: 56193 AN: 1111946

Other (OTH) AF: 0.0662 AC: 3999 AN: 60384

GnomAD4 genome AF: 0.0715 AC: 10894 AN: 152304 Hom.: 462 Cov.: 33 AF XY: 0.0724 AC XY: 5394 AN XY: 74480

African (AFR) AF: 0.0954 AC: 3963 AN: 41552

American (AMR) AF: 0.107 AC: 1633 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3470

East Asian (EAS) AF: 0.118 AC: 611 AN: 5164

South Asian (SAS) AF: 0.140 AC: 674 AN: 4822

European-Finnish (FIN) AF: 0.0218 AC: 232 AN: 10626

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0500 AC: 3399 AN: 68038

Other (OTH) AF: 0.0699 AC: 148 AN: 2116

Alfa AF: 0.0611 Hom.: 950

Bravo AF: 0.0803

TwinsUK AF: 0.0574 AC: 213

ALSPAC AF: 0.0501 AC: 193

ESP6500AA AF: 0.0903 AC: 398

ESP6500EA AF: 0.0542 AC: 466

ExAC AF: 0.0819 AC: 9949

EpiCase AF: 0.0505

EpiControl AF: 0.0519

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Stromme syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.2
DANN	Benign	0.38
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.054	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.90	T
PhyloP100		1.7
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.074
Sift	Benign	0.30	T
Sift4G	Benign	0.30	T
Polyphen		0.019	B
Vest4		0.0070
MPC		0.053
ClinPred		0.0030	T
GERP RS		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.064
Mutation Taster		=98/2	polymorphism (auto)

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: rs3795524; hg19: chr1-214813782; COSMIC: COSV65277629;