9-34611034-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_148178.3(RPP25L):​c.263G>A​(p.Arg88His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

RPP25L
NM_148178.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.555
Variant links:
Genes affected
RPP25L (HGNC:19909): (ribonuclease P/MRP subunit p25 like) This gene encodes a protein that appears to belong to a family of evolutionarily related proteins (DUF78), that may share one or more domains in common. Members of this family are small archaebacterial proteins with no known function. Alternative splicing has been observed at this locus and two variants, both encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04633665).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPP25LNM_148178.3 linkc.263G>A p.Arg88His missense_variant Exon 2 of 2 ENST00000378959.9 NP_680544.1 Q8N5L8
RPP25LNM_148179.3 linkc.263G>A p.Arg88His missense_variant Exon 2 of 2 NP_680545.1 Q8N5L8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPP25LENST00000378959.9 linkc.263G>A p.Arg88His missense_variant Exon 2 of 2 1 NM_148178.3 ENSP00000368242.4 Q8N5L8
RPP25LENST00000297613.4 linkc.263G>A p.Arg88His missense_variant Exon 2 of 2 2 ENSP00000297613.4 Q8N5L8

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152120
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251002
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135772
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000335
AC:
49
AN:
1461770
Hom.:
0
Cov.:
31
AF XY:
0.0000248
AC XY:
18
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000432
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152120
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000761
Hom.:
0
Bravo
AF:
0.0000264
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000218
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 15, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.263G>A (p.R88H) alteration is located in exon 2 (coding exon 1) of the RPP25L gene. This alteration results from a G to A substitution at nucleotide position 263, causing the arginine (R) at amino acid position 88 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.056
T;T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.71
.;T
M_CAP
Benign
0.0047
T
MetaRNN
Benign
0.046
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.51
N;N
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.6
N;N
REVEL
Benign
0.072
Sift
Benign
0.54
T;T
Sift4G
Benign
0.54
T;T
Polyphen
0.047
B;B
Vest4
0.076
MVP
0.068
MPC
0.51
ClinPred
0.054
T
GERP RS
3.7
Varity_R
0.069
gMVP
0.45

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.

Other links and lift over

dbSNP: rs756300443; hg19: chr9-34611031; COSMIC: COSV99426827; COSMIC: COSV99426827; API