X-101145086-A-G

Position:

chrX-101145086-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001386188.2(CENPI):c.1588A>G(p.Met530Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,203,073 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

CENPI
NM_001386188.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.280

Variant links:

Genes affected

CENPI (HGNC:3968): (centromere protein I) This gene encodes a centromere protein that is a component of the CENPA-NAC (nucleosome-associated) complex. This complex is critical for accurate chromosome alignment and segregation and it ensures proper mitotic progression. This protein regulates the recruitment of kinetochore-associated proteins that are required to generate the spindle checkpoint signal. The product of this gene is involved in the response of gonadal tissues to follicle-stimulating hormone. Mutations in this gene may be involved in human X-linked disorders of gonadal development and gametogenesis. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 13. [provided by RefSeq, Jan 2016]

CENPI links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07287875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPI	NM_001386188.2 linkuse as main transcript	c.1588A>G	p.Met530Val	missense_variant	17/22	ENST00000682095.1	NP_001373117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPI	ENST00000682095.1 linkuse as main transcript	c.1588A>G	p.Met530Val	missense_variant	17/22		NM_001386188.2	ENSP00000507927	P2	Q92674-1
CENPI	ENST00000372927.5 linkuse as main transcript	c.1588A>G	p.Met530Val	missense_variant	16/21	5		ENSP00000362018	P2	Q92674-1
CENPI	ENST00000684367.1 linkuse as main transcript	c.1588A>G	p.Met530Val	missense_variant	18/23			ENSP00000507595	P2	Q92674-1
CENPI	ENST00000423383.3 linkuse as main transcript	c.1588A>G	p.Met530Val	missense_variant	17/21	5		ENSP00000399274	A2

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112288

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34440

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000190

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000564

AC:

AN:

177296

Hom.:

AF XY:

0.00

AC XY:

AN XY:

62212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000387

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.17e-7

AC:

AN:

1090785

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

356761

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112288

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34440

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000190

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The c.1588A>G (p.M530V) alteration is located in exon 16 (coding exon 15) of the CENPI gene. This alteration results from a A to G substitution at nucleotide position 1588, causing the methionine (M) at amino acid position 530 to be replaced by a valine (V). 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

0.072

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.60

DANN

Benign

0.58

DEOGEN2

Benign

0.044

T;T

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.61

.;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.073

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

0.53

N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.88

N;N

REVEL

Benign

0.048

Sift

Benign

0.40

T;T

Sift4G

Benign

0.93

T;T

Polyphen

0.0010

B;B

Vest4

0.15

MutPred

0.51

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.18

MPC

0.38

ClinPred

0.021

GERP RS

-2.1

Varity_R

0.075

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over