X-101109991-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001386188.2(CENPI):c.584A>C(p.Asp195Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CENPI NM_001386188.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPI	NM_001386188.2	c.584A>C	p.Asp195Ala	missense_variant	6/22	ENST00000682095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPI	ENST00000682095.1	c.584A>C	p.Asp195Ala	missense_variant	6/22		NM_001386188.2	P2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2021

The c.584A>C (p.D195A) alteration is located in exon 5 (coding exon 4) of the CENPI gene. This alteration results from a A to C substitution at nucleotide position 584, causing the aspartic acid (D) at amino acid position 195 to be replaced by an alanine (A). 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	0.14
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T;.;T
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.058	T;T;T
Polyphen		0.41	.;B;B
Vest4		0.44
MutPred		0.65		Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP		0.43
MPC		0.54
ClinPred		0.92	D
GERP RS		5.4
Varity_R		0.41
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-100364980;