rs115334254

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 13/17 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 Likely 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
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001396110.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHP2	NM_017838.4	MANE Select	c.351C>T	p.Ala117Ala	synonymous	Exon 4 of 4	NP_060308.1	Q9NX24
	RMND5B	NM_022762.5	MANE Select	c.*1792G>A		3_prime_UTR	Exon 11 of 11	NP_073599.2
	NHP2	NM_001396110.1		c.479C>T	p.Pro160Leu	missense	Exon 5 of 5	NP_001383039.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHP2	ENST00000274606.8	TSL:1 MANE Select	c.351C>T	p.Ala117Ala	synonymous	Exon 4 of 4	ENSP00000274606.4	Q9NX24
	RMND5B	ENST00000313386.9	TSL:1 MANE Select	c.*1792G>A		3_prime_UTR	Exon 11 of 11	ENSP00000320623.4	Q96G75-1
	NHP2	ENST00000314397.9	TSL:2	c.245C>T	p.Pro82Leu	missense	Exon 3 of 3	ENSP00000366276.2	J3QSY4

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

GnomAD2 exomes AF: 0.00244 AC: 611 AN: 250884 AF XY: 0.00169

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 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

African (AFR) AF: 0.0320 AC: 1070 AN: 33466

American (AMR) AF: 0.00137 AC: 61 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26114

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39682

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000639 AC: 71 AN: 1111764

Other (OTH) AF: 0.00139 AC: 84 AN: 60372

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

African (AFR) AF: 0.0326 AC: 1353 AN: 41546

American (AMR) AF: 0.00248 AC: 38 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68026

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00363 Hom.: 15

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Dyskeratosis congenita (2)
-	-	2	not provided (2)
-	-	1	Dyskeratosis congenita, autosomal recessive 1;C3151441:Dyskeratosis congenita, autosomal recessive 2 (1)
-	-	1	Dyskeratosis congenita, autosomal recessive 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
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
PhyloP100		-3.7
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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs115334254; hg19: chr5-177576825;