Genetic Variant NOL8:c.-593A>C (chr9-92325542-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001286969.1(CENPP):c.-611T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 154,472 control chromosomes in the GnomAD database, including 14,869 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.41 ( 14739 hom., cov: 32)

Exomes 𝑓: 0.28 ( 130 hom. )

Consequence

CENPP
NM_001286969.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.585

Publications

10 publications found

Variant links:

Genes affected

NOL8 (HGNC:23387): (nucleolar protein 8) NOL8 binds Ras-related GTP-binding proteins (see MIM 608267) and plays a role in cell growth (Sekiguchi et al., 2004 [PubMed 14660641]).[supplied by OMIM, Mar 2008]

NOL8 links:

CENPP (HGNC:32933): (centromere protein P) CENPP is a subunit of a CENPH (MIM 605607)-CENPI (MIM 300065)-associated centromeric complex that targets CENPA (MIM 117139) to centromeres and is required for proper kinetochore function and mitotic progression (Okada et al., 2006 [PubMed 16622420]).[supplied by OMIM, Mar 2008]

CENPP links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286969.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CENPP	NM_001286969.1		c.-611T>G	5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001273898.1
CENPP	NM_001286969.1		c.-611T>G	5_prime_UTR	Exon 1 of 7	NP_001273898.1
NOL8	NM_017948.6	MANE Select	c.-285A>C	upstream_gene	N/A	NP_060418.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NOL8	ENST00000358855.8	TSL:1	c.-593A>C	5_prime_UTR	Exon 1 of 18	ENSP00000351723.4	Q76FK4-2
NOL8	ENST00000421075.6	TSL:5	c.-273A>C	5_prime_UTR	Exon 1 of 7	ENSP00000390143.2	A0A0A0MSJ1
NOL8	ENST00000958984.1		c.-1381A>C	5_prime_UTR	Exon 1 of 16	ENSP00000629043.1

Frequencies

GnomAD3 genomes

AF:

0.405

AC:

61530

AN:

151830

Hom.:

14723

Cov.:

show subpopulations

Gnomad AFR

AF:

0.663

Gnomad AMI

AF:

0.527

Gnomad AMR

AF:

0.290

Gnomad ASJ

AF:

0.379

Gnomad EAS

AF:

0.106

Gnomad SAS

AF:

0.224

Gnomad FIN

AF:

0.278

Gnomad MID

AF:

0.561

Gnomad NFE

AF:

0.329

Gnomad OTH

AF:

0.392

GnomAD4 exome

AF:

0.284

AC:

716

AN:

2524

Hom.:

130

Cov.:

AF XY:

0.273

AC XY:

404

AN XY:

1478

show subpopulations

African (AFR)

AF:

0.779

AC:

AN:

American (AMR)

AF:

0.284

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.402

AC:

AN:

East Asian (EAS)

AF:

0.208

AC:

AN:

South Asian (SAS)

AF:

0.217

AC:

143

AN:

660

European-Finnish (FIN)

AF:

0.202

AC:

AN:

Middle Eastern (MID)

AF:

0.300

AC:

AN:

European-Non Finnish (NFE)

AF:

0.293

AC:

397

AN:

1356

Other (OTH)

AF:

0.288

AC:

AN:

118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.405

AC:

61584

AN:

151948

Hom.:

14739

Cov.:

AF XY:

0.396

AC XY:

29414

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.663

AC:

27469

AN:

41410

American (AMR)

AF:

0.290

AC:

4427

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

1315

AN:

3466

East Asian (EAS)

AF:

0.106

AC:

549

AN:

5156

South Asian (SAS)

AF:

0.223

AC:

1073

AN:

4820

European-Finnish (FIN)

AF:

0.278

AC:

2944

AN:

10578

Middle Eastern (MID)

AF:

0.562

AC:

164

AN:

292

European-Non Finnish (NFE)

AF:

0.329

AC:

22354

AN:

67944

Other (OTH)

AF:

0.385

AC:

808

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1683

3366

5049

6732

8415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.359

Hom.:

29104

Bravo

AF:

0.419

Asia WGS

AF:

0.182

AC:

632

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.6

(source)

DANN

Benign

0.66

PhyloP100

-0.58

PromoterAI

-0.027

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over