rs146261631

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_018648.4(NOP10):c.34G>C(p.Asp12His) variant causes a missense change. The variant allele was found at a frequency of 0.0107 in 1,614,014 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D12E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0083 ( 12 hom., cov: 32)

Exomes 𝑓: 0.011 ( 109 hom. )

Consequence

NOP10
NM_018648.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:8

Conservation

PhyloP100: 4.80

Publications

11 publications found

Variant links:

Genes affected

NOP10 (HGNC:14378): (NOP10 ribonucleoprotein) This gene is a member of the H/ACA snoRNPs (small nucleolar ribonucleoproteins) gene family. snoRNPs are involved in various aspects of rRNA processing and modification and have been classified into two families: C/D and H/ACA. The H/ACA snoRNPs also include the DKC1, NOLA1 and NOLA2 proteins. These four H/ACA snoRNP proteins localize to the dense fibrillar components of nucleoli and to coiled (Cajal) bodies in the nucleus. Both 18S rRNA production and rRNA pseudouridylation are impaired if any one of the four proteins is depleted. The four H/ACA snoRNP proteins are also components of the telomerase complex. This gene encodes a protein related to Saccharomyces cerevisiae Nop10p. [provided by RefSeq, Jul 2008]

NOP10 Gene-Disease associations (from GenCC):

dyskeratosis congenita, autosomal recessive 1
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

NOP10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_018648.4

BP4

Computational evidence support a benign effect (MetaRNN=0.010433614).

BP6

Variant 15-34343040-C-G is Benign according to our data. Variant chr15-34343040-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235529.

BS2

High Homozygotes in GnomAd4 at 12 AR,Unknown,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOP10	NM_018648.4 link	c.34G>C	p.Asp12His	missense_variant	Exon 1 of 2	ENST00000328848.6	NP_061118.1	Q9NPE3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOP10	ENST00000328848.6 link	c.34G>C	p.Asp12His	missense_variant	Exon 1 of 2	1	NM_018648.4	ENSP00000332198.5		Q9NPE3

Frequencies

GnomAD3 genomes

AF:

0.00829

AC:

1261

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00786

Gnomad FIN

AF:

0.0250

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.00985

AC:

2476

AN:

251472

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.0119

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0279

Gnomad NFE exome

AF:

0.0122

Gnomad OTH exome

AF:

0.00831

GnomAD4 exome

AF:

0.0109

AC:

15976

AN:

1461716

Hom.:

109

Cov.:

AF XY:

0.0108

AC XY:

7869

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33478

American (AMR)

AF:

0.00228

AC:

102

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

287

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00718

AC:

619

AN:

86252

European-Finnish (FIN)

AF:

0.0279

AC:

1489

AN:

53416

Middle Eastern (MID)

AF:

0.00641

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0115

AC:

12773

AN:

1111852

Other (OTH)

AF:

0.0101

AC:

608

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

865

1730

2596

3461

4326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.00827

AC:

1259

AN:

152298

Hom.:

Cov.:

AF XY:

0.00837

AC XY:

623

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00178

AC:

AN:

41566

American (AMR)

AF:

0.00275

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00746

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0250

AC:

265

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0115

AC:

785

AN:

68026

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

131

196

262

327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0111

Hom.:

Bravo

AF:

0.00592

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0119

AC:

102

ExAC

AF:

0.00974

AC:

1183

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00938

EpiControl

AF:

0.0106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Mar 16, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 02, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NOP10: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita, autosomal recessive 1

Benign:2

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9

Pathogenic:1

Oct 27, 2024

Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The D12H missense variant in NOP10 (exon 1) was identified in 9 of 17 family members screened after its initial detection in a proband with bone marrow failure. Familial segregation analysis revealed a history of malignancies and early death. One adult with same variant progressed from bone marrow failure to myelodysplasia. All individuals harboring the variant exhibited similar abnormal skin changes. In silico prediction tools support a deleterious effect: SIFT and MISTIC classified the variant as damaging, and PolyPhen-2 predicted it to be possibly damaging. These findings suggest that D12H may be a pathogenic variant contributing to a heritable bone marrow failure syndrome. -

not specified

Benign:1

May 06, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.42

T;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;.

MetaRNN

Benign

0.010

T;T

MetaSVM

Uncertain

-0.052

PhyloP100

4.8

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.27

Sift

Uncertain

0.014

D;.

Sift4G

Uncertain

0.013

D;.

Polyphen

0.86

P;.

Vest4

0.49

MPC

1.1

ClinPred

0.046

GERP RS

5.0

PromoterAI

-0.058

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.46

gMVP

0.46

Mutation Taster

=83/17

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over