rs145890370

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_017838.4(NHP2):c.302G>A(p.Arg101Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00759 in 1,613,994 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0078 ( 64 hom. )

Consequence

NHP2
NM_017838.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.73

Variant links:

Genes affected

NHP2 (HGNC:14377): (NHP2 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 NOLA3 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 Nhp2p. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2008]

NHP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047282577).

BP6

Variant 5-178150922-C-T is Benign according to our data. Variant chr5-178150922-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-178150922-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NHP2	NM_017838.4 linkuse as main transcript	c.302G>A	p.Arg101Gln	missense_variant	3/4	ENST00000274606.8
NHP2	NM_001396110.1 linkuse as main transcript	c.302G>A	p.Arg101Gln	missense_variant	3/5
NHP2	NM_001034833.2 linkuse as main transcript	c.231-1084G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHP2	ENST00000274606.8 linkuse as main transcript	c.302G>A	p.Arg101Gln	missense_variant	3/4	1	NM_017838.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00592

AC:

900

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.0749

Gnomad AMR

AF:

0.00675

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00926

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00480

AC:

1207

AN:

251494

Hom.:

AF XY:

0.00492

AC XY:

669

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00416

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00832

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00777

AC:

11358

AN:

1461728

Hom.:

Cov.:

AF XY:

0.00760

AC XY:

5528

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00119

Gnomad4 AMR exome

AF:

0.00445

Gnomad4 ASJ exome

AF:

0.00203

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000707

Gnomad4 FIN exome

AF:

0.00114

Gnomad4 NFE exome

AF:

0.00948

Gnomad4 OTH exome

AF:

0.00623

GnomAD4 genome

AF:

0.00591

AC:

900

AN:

152266

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

406

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.00674

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00926

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00769

Hom.:

Bravo

AF:

0.00637

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.00461

AC:

560

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.00907

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2020	This variant is associated with the following publications: (PMID: 22752289) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	NHP2: BP4, BS1 -

Dyskeratosis congenita

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 17, 2016

- -

NHP2-related condition

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T;T;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

D;D;D;D

MetaRNN

Benign

0.0047

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.053

Sift

Benign

0.14

T;T;T;T

Sift4G

Benign

0.50

T;T;.;.

Polyphen

0.0040

B;.;.;.

Vest4

0.40

MVP

0.64

MPC

0.46

ClinPred

0.011

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.095

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.25

Position offset: -34

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