X-101127186-G-A

Position:

• chrX-101127186-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001386188.2(CENPI):​c.826G>A​(p.Val276Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000997 in 1,189,898 control chromosomes in the GnomAD database, including 6 homozygotes. There are 342 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., 161 hem., cov: 23)
  • Exomes 𝑓: 0.00058 (2 hom. 181 hem.)
• Consequence: CENPI NM_001386188.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0820

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006650746).
• BP6: Variant X-101127186-G-A is Benign according to our data. Variant chrX-101127186-G-A is described in ClinVar as [Benign]. Clinvar id is 734919.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00497 (556/111812) while in subpopulation AFR AF= 0.0164 (505/30802). AF 95% confidence interval is 0.0152. There are 4 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPI	NM_001386188.2	c.826G>A	p.Val276Met	missense_variant	10/22	ENST00000682095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPI	ENST00000682095.1	c.826G>A	p.Val276Met	missense_variant	10/22		NM_001386188.2	P2

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 555 AN: 111759 Hom.: 4 Cov.: 23 AF XY: 0.00471 AC XY: 160 AN XY: 33971

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00411

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000278

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00847

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00198

GnomAD3 exomes AF: 0.00153 AC: 265 AN: 172702 Hom.: 3 AF XY: 0.00106 AC XY: 62 AN XY: 58434

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000782

Gnomad SAS exome AF: 0.0000601

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000962

GnomAD4 exome AF: 0.000584 AC: 630 AN: 1078086 Hom.: 2 Cov.: 28 AF XY: 0.000520 AC XY: 181 AN XY: 347744

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.00124

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000334

Gnomad4 SAS exome AF: 0.0000603

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000722

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00497 AC: 556 AN: 111812 Hom.: 4 Cov.: 23 AF XY: 0.00473 AC XY: 161 AN XY: 34034

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.00411

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000279

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00196

Alfa AF: 0.000676 Hom.: 25

Bravo AF: 0.00617

ESP6500AA AF: 0.0151 AC: 58

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00169 AC: 205

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.2
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.66	T;.;T
MetaRNN	Benign	0.0067	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.038	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.24	.;B;B
Vest4		0.25
MVP		0.17
MPC		0.51
ClinPred		0.013	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.079
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144553945; hg19: chrX-100382175; COSMIC: COSV54501552;