15-34343040-C-G

Position:

chr15-34343040-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The ENST00000328848.6(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 Likely benign (★★). 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
ENST00000328848.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.80

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 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, 4 uncertain in ENST00000328848.6

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 [Likely_benign]. Clinvar id is 235529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-34343040-C-G is described in Lovd as [Likely_benign]. Variant chr15-34343040-C-G is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOP10	NM_018648.4 linkuse as main transcript	c.34G>C	p.Asp12His	missense_variant	1/2	ENST00000328848.6	NP_061118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOP10	ENST00000328848.6 linkuse as main transcript	c.34G>C	p.Asp12His	missense_variant	1/2	1	NM_018648.4	ENSP00000332198	P4

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

GnomAD3 exomes

AF:

0.00985

AC:

2476

AN:

251472

Hom.:

AF XY:

0.0102

AC XY:

1389

AN XY:

135922

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 SAS exome

AF:

0.00686

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

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.00228

Gnomad4 ASJ exome

AF:

0.0110

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00718

Gnomad4 FIN exome

AF:

0.0279

Gnomad4 NFE exome

AF:

0.0115

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.00827

AC:

1259

AN:

152298

Hom.:

Cov.:

AF XY:

0.00837

AC XY:

623

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00746

Gnomad4 FIN

AF:

0.0250

Gnomad4 NFE

AF:

0.0115

Gnomad4 OTH

AF:

0.00616

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: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NOP10: BS1, BS2 -

Dyskeratosis congenita, autosomal recessive 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 06, 2016

- -

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

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

MutationTaster

Benign

1.0

D;D

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

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.46

gMVP

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over