rs375193070

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022909.4(CENPH):c.20T>G(p.Met7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000649 in 1,601,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

CENPH
NM_022909.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0710

Publications

1 publications found

Variant links:

Genes affected

CENPH (HGNC:17268): (centromere protein H) Centromere and kinetochore proteins play a critical role in centromere structure, kinetochore formation, and sister chromatid separation. The protein encoded by this gene colocalizes with inner kinetochore plate proteins CENP-A and CENP-C in both interphase and metaphase. It localizes outside of centromeric heterochromatin, where CENP-B is localized, and inside the kinetochore corona, where CENP-E is localized during prometaphase. It is thought that this protein can bind to itself, as well as to CENP-A, CENP-B or CENP-C. Multimers of the protein localize constitutively to the inner kinetochore plate and play an important role in the organization and function of the active centromere-kinetochore complex. [provided by RefSeq, Jul 2008]

CENPH links:

ENSG00000295746 (HGNC:):

ENSG00000295746 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0052981675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPH	NM_022909.4 link	c.20T>G	p.Met7Arg	missense_variant	Exon 1 of 9	ENST00000283006.7	NP_075060.1	Q9H3R5A0A0S2Z5T0
LOC112267932	XR_002956215.2 link	n.-177A>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPH	ENST00000283006.7 link	c.20T>G	p.Met7Arg	missense_variant	Exon 1 of 9	1	NM_022909.4	ENSP00000283006.2		Q9H3R5

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000132

AC:

AN:

227116

AF XY:

0.0000161

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000296

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000559

AC:

AN:

1449562

Hom.:

Cov.:

AF XY:

0.0000527

AC XY:

AN XY:

720388

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33254

American (AMR)

AF:

0.00

AC:

AN:

43700

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25908

East Asian (EAS)

AF:

0.00

AC:

AN:

39328

South Asian (SAS)

AF:

0.00

AC:

AN:

84754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4308

European-Non Finnish (NFE)

AF:

0.0000713

AC:

AN:

1108226

Other (OTH)

AF:

0.00

AC:

AN:

59792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000151

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41454

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000704

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.20T>G (p.M7R) alteration is located in exon 1 (coding exon 1) of the CENPH gene. This alteration results from a T to G substitution at nucleotide position 20, causing the methionine (M) at amino acid position 7 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.2

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.0099

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0089

LIST_S2

Benign

0.39

T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

PhyloP100

0.071

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.070

N;N

REVEL

Benign

0.038

Sift

Benign

0.16

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.0

B;B

Vest4

0.13

MVP

0.22

MPC

0.071

ClinPred

0.039

GERP RS

1.3

PromoterAI

-0.031

Neutral

(source)

Varity_R

0.23

gMVP

0.065

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs375193070

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over