X-101127253-G-A

Variant names:

• chrX-101127253-G-A
• rs1369005501
• NM_001386188.2:c.893G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001386188.2(CENPI):​c.893G>A​(p.Arg298His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000472 in 1,059,950 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000047 (0 hom. 3 hem.)
• Consequence: CENPI NM_001386188.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.534
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• idiopathic steroid-sensitive nephrotic syndrome

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059655577).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386188.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPI	NM_001386188.2	MANE Select	c.893G>A	p.Arg298His	missense	Exon 10 of 22	NP_001373117.1	Q92674-1
	CENPI	NM_006733.3		c.893G>A	p.Arg298His	missense	Exon 9 of 21	NP_006724.2	Q92674-1
	CENPI	NM_001318521.2		c.893G>A	p.Arg298His	missense	Exon 10 of 21	NP_001305450.1	A0A8C8KX99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPI	ENST00000682095.1	MANE Select	c.893G>A	p.Arg298His	missense	Exon 10 of 22	ENSP00000507927.1	Q92674-1
	CENPI	ENST00000372927.5	TSL:5	c.893G>A	p.Arg298His	missense	Exon 9 of 21	ENSP00000362018.1	Q92674-1
	CENPI	ENST00000684367.1		c.893G>A	p.Arg298His	missense	Exon 11 of 23	ENSP00000507595.1	Q92674-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000636 AC: 1 AN: 157251 AF XY: 0.0000193

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: 0.0000135

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000472 AC: 5 AN: 1059950 Hom.: 0 Cov.: 29 AF XY: 0.00000887 AC XY: 3 AN XY: 338296

African (AFR) AF: 0.0000808 AC: 2 AN: 24743

American (AMR) AF: 0.00 AC: 0 AN: 28359

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17844

East Asian (EAS) AF: 0.00 AC: 0 AN: 29670

South Asian (SAS) AF: 0.00 AC: 0 AN: 45705

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2733

European-Non Finnish (NFE) AF: 0.00000363 AC: 3 AN: 827128

Other (OTH) AF: 0.00 AC: 0 AN: 44270

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000869 Hom.: 1

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.8
DANN	Benign	0.94
DEOGEN2	Benign	0.048	T
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L
PhyloP100		-0.53
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.014
Sift	Benign	0.33	T
Sift4G	Benign	0.31	T
Polyphen		0.0040	B
Vest4		0.061
MVP		0.17
MPC		0.47
ClinPred		0.11	T
GERP RS		0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.25
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1369005501; hg19: chrX-100382242; COSMIC: COSV54501189;