rs11558534

chr16-67833836-G-T

Variant summary

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

The NM_025082.4(CENPT):c.24C>A(p.Ser8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 1,568,330 control chromosomes in the GnomAD database, including 1,273 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. S8N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (96 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1177 hom.)
• Consequence: CENPT NM_025082.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0980

Genes affected

CENPT (HGNC:25787): (centromere protein T) The centromere is a specialized chromatin domain, present throughout the cell cycle, that acts as a platform on which the transient assembly of the kinetochore occurs during mitosis. All active centromeres are characterized by the presence of long arrays of nucleosomes in which CENPA (MIM 117139) replaces histone H3 (see MIM 601128). CENPT is an additional factor required for centromere assembly (Foltz et al., 2006 [PubMed 16622419]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020076036).
• BP6: Variant 16-67833836-G-T is Benign according to our data. Variant chr16-67833836-G-T is described in ClinVar as [Benign]. Clinvar id is 1209722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPT	NM_025082.4	c.24C>A	p.Ser8Arg	missense_variant	4/16	ENST00000562787.6
CENPT	XM_047434686.1	c.24C>A	p.Ser8Arg	missense_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPT	ENST00000562787.6	c.24C>A	p.Ser8Arg	missense_variant	4/16	2	NM_025082.4	P1

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4445 AN: 152202 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.00924

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00910

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0449

GnomAD3 exomes AF: 0.0302 AC: 5809 AN: 192428 Hom.: 123 AF XY: 0.0311 AC XY: 3341 AN XY: 107268

Gnomad AFR exome AF: 0.00764

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0550

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0112

Gnomad FIN exome AF: 0.0253

Gnomad NFE exome AF: 0.0432

Gnomad OTH exome AF: 0.0397

GnomAD4 exome AF: 0.0377 AC: 53382 AN: 1416010 Hom.: 1177 Cov.: 31 AF XY: 0.0372 AC XY: 26163 AN XY: 703228

Gnomad4 AFR exome AF: 0.00858

Gnomad4 AMR exome AF: 0.0235

Gnomad4 ASJ exome AF: 0.0589

Gnomad4 EAS exome AF: 0.0000288

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.0274

Gnomad4 NFE exome AF: 0.0418

Gnomad4 OTH exome AF: 0.0396

GnomAD4 genome AF: 0.0292 AC: 4442 AN: 152320 Hom.: 96 Cov.: 32 AF XY: 0.0276 AC XY: 2059 AN XY: 74492

Gnomad4 AFR AF: 0.00924

Gnomad4 AMR AF: 0.0351

Gnomad4 ASJ AF: 0.0541

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.0252

Gnomad4 NFE AF: 0.0416

Gnomad4 OTH AF: 0.0444

Alfa AF: 0.0425 Hom.: 170

Bravo AF: 0.0284

TwinsUK AF: 0.0461 AC: 171

ALSPAC AF: 0.0426 AC: 164

ESP6500AA AF: 0.00845 AC: 34

ESP6500EA AF: 0.0388 AC: 325

ExAC AF: 0.0297 AC: 3562

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Short stature and microcephaly with genital anomalies Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

CENPT-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	1.7
Dann	Benign	0.94
DEOGEN2	Benign	0.0088	T;T;.;T;.;T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.025	N
MetaRNN	Benign	0.0020	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N;N;.;N;N;D;D
Sift	Benign	0.089	T;T;.;T;T;T;T
Sift4G	Benign	0.12	T;T;D;T;.;.;.
Polyphen		0.0070	B;B;.;.;.;.;.
Vest4		0.064
MutPred		0.094		Loss of phosphorylation at S8 (P = 0.0096);Loss of phosphorylation at S8 (P = 0.0096);Loss of phosphorylation at S8 (P = 0.0096);Loss of phosphorylation at S8 (P = 0.0096);Loss of phosphorylation at S8 (P = 0.0096);Loss of phosphorylation at S8 (P = 0.0096);Loss of phosphorylation at S8 (P = 0.0096);
MPC		0.10
ClinPred		0.0059	T
GERP RS		1.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.084
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11558534; hg19: chr16-67867739; COSMIC: COSV54649739; COSMIC: COSV54649739;