rs145890370

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_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. 14/23 in silico tools predict 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. R101G) has been classified as Uncertain significance.

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:9

Conservation

PhyloP100: 2.73

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

dyskeratosis congenita, autosomal recessive 2
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
dyskeratosis congenita
Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen

NHP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP6

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

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NHP2	NM_017838.4 link	c.302G>A	p.Arg101Gln	missense_variant	Exon 3 of 4	ENST00000274606.8	NP_060308.1
NHP2	NM_001396110.1 link	c.302G>A	p.Arg101Gln	missense_variant	Exon 3 of 5		NP_001383039.1
NHP2	NM_001034833.2 link	c.231-1084G>A		intron_variant	Intron 2 of 2		NP_001030005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHP2	ENST00000274606.8 link	c.302G>A	p.Arg101Gln	missense_variant	Exon 3 of 4	1	NM_017838.4	ENSP00000274606.4

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

GnomAD2 exomes

AF:

0.00480

AC:

1207

AN:

251494

AF XY:

0.00492

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 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

African (AFR)

AF:

0.00119

AC:

AN:

33478

American (AMR)

AF:

0.00445

AC:

199

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000707

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00948

AC:

10542

AN:

1111864

Other (OTH)

AF:

0.00623

AC:

376

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

576

1152

1727

2303

2879

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

406

812

1218

1624

2030

<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:

0.00591

AC:

900

AN:

152266

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

406

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41550

American (AMR)

AF:

0.00674

AC:

103

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00926

AC:

630

AN:

68028

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

140

187

234

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:

0.00722

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 23, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22752289) -

Sep 08, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NHP2: BP4, BS2 -

Dyskeratosis congenita

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 04, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Dyskeratosis congenita, autosomal recessive 2

Benign:1

Jul 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 17, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NHP2-related disorder

Benign:1

Aug 12, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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;.;.;.

PhyloP100

2.7

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

Mutation Taster

=96/4

polymorphism

(source)

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

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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