rs115334254

Variant names:

• chr5-178149824-G-A
• rs115334254
• NM_017838.4:c.351C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001396110.1(NHP2):​c.479C>T​(p.Pro160Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,613,720 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P160P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0093 (20 hom., cov: 33)
  • Exomes 𝑓: 0.00089 (18 hom.)
• Consequence: NHP2 NM_001396110.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.70

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]

RMND5B (HGNC:26181): (required for meiotic nuclear division 5 homolog B) Predicted to enable metal ion binding activity and ubiquitin protein ligase activity. Predicted to contribute to ubiquitin-protein transferase activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020320415).
• BP6: Variant 5-178149824-G-A is Benign according to our data. Variant chr5-178149824-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00932 (1419/152302) while in subpopulation AFR AF= 0.0326 (1353/41546). AF 95% confidence interval is 0.0311. There are 20 homozygotes in gnomad4. There are 714 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHP2	NM_017838.4	c.351C>T	p.Ala117Ala	synonymous_variant	Exon 4 of 4	ENST00000274606.8	NP_060308.1
RMND5B	NM_022762.5	c.*1792G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000313386.9	NP_073599.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHP2	ENST00000274606.8	c.351C>T	p.Ala117Ala	synonymous_variant	Exon 4 of 4	1	NM_017838.4	ENSP00000274606.4
RMND5B	ENST00000313386.9	c.*1792G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_022762.5	ENSP00000320623.4

Frequencies

GnomAD3 genomes AF: 0.00933 AC: 1420 AN: 152184 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00244 AC: 611 AN: 250884 Hom.: 16 AF XY: 0.00169 AC XY: 229 AN XY: 135568

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000886 AC: 1295 AN: 1461418 Hom.: 18 Cov.: 31 AF XY: 0.000791 AC XY: 575 AN XY: 726930

Gnomad4 AFR exome AF: 0.0320

Gnomad4 AMR exome AF: 0.00137

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00932 AC: 1419 AN: 152302 Hom.: 20 Cov.: 33 AF XY: 0.00959 AC XY: 714 AN XY: 74464

Gnomad4 AFR AF: 0.0326

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00197 Hom.: 9

Bravo AF: 0.0104

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0356 AC: 157

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00304 AC: 369

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 11, 2021

GeneDx

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

- -

Dyskeratosis congenita Benign:2

Sep 07, 2023

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita, autosomal recessive 2 Benign:1

May 07, 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;C3151441:Dyskeratosis congenita, autosomal recessive 2 Benign:1

May 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.41
DANN	Benign	0.86
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.064
Sift	Benign	0.39	T
Sift4G	Benign	0.43	T
Vest4		0.20
MVP		0.32
ClinPred		0.012	T
GERP RS		-11
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

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

Other links and lift over

dbSNP: rs115334254; hg19: chr5-177576825;