chr1-214641955-A-G

Position:

• chr1-214641955-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_016343.4(CENPF):​c.3617A>G​(p.Tyr1206Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,595,864 control chromosomes in the GnomAD database, including 10 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (10 hom.)
• Consequence: CENPF NM_016343.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.175

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003427714).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00218 (332/152326) while in subpopulation AMR AF= 0.00333 (51/15300). AF 95% confidence interval is 0.00272. There are 0 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPF	NM_016343.4	c.3617A>G	p.Tyr1206Cys	missense_variant	12/20	ENST00000366955.8	NP_057427.3
CENPF	XM_017000086.3	c.3617A>G	p.Tyr1206Cys	missense_variant	12/20		XP_016855575.1
CENPF	XM_011509082.4	c.3617A>G	p.Tyr1206Cys	missense_variant	12/19		XP_011507384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPF	ENST00000366955.8	c.3617A>G	p.Tyr1206Cys	missense_variant	12/20	1	NM_016343.4	ENSP00000355922	P2
CENPF	ENST00000706765.1	c.3617A>G	p.Tyr1206Cys	missense_variant	12/19			ENSP00000516538	A2

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00255 AC: 589 AN: 231036 Hom.: 0 AF XY: 0.00256 AC XY: 321 AN XY: 125332

Gnomad AFR exome AF: 0.000530

Gnomad AMR exome AF: 0.000995

Gnomad ASJ exome AF: 0.00831

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000539

Gnomad FIN exome AF: 0.00210

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00329 AC: 4753 AN: 1443538 Hom.: 10 Cov.: 35 AF XY: 0.00321 AC XY: 2304 AN XY: 717586

Gnomad4 AFR exome AF: 0.000436

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00777

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000757

Gnomad4 FIN exome AF: 0.00236

Gnomad4 NFE exome AF: 0.00370

Gnomad4 OTH exome AF: 0.00333

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74490

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00306

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00332 Hom.: 8

Bravo AF: 0.00235

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00263 AC: 319

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 29, 2016

- -

Stromme syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 27, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.3
DANN	Benign	0.80
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.015
Sift	Benign	0.15	T
Sift4G	Benign	0.19	T
Polyphen		0.13	B
Vest4		0.26
MVP		0.36
MPC		0.067
ClinPred		0.0019	T
GERP RS		1.7
Varity_R		0.075
gMVP		0.22

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: rs144237457; hg19: chr1-214815298;