chr15-74956388-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_017793.3(RPP25):​c.196G>T​(p.Val66Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,451,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RPP25
NM_017793.3 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64
Variant links:
Genes affected
RPP25 (HGNC:30361): (ribonuclease P and MRP subunit p25) Enables ribonuclease P RNA binding activity. Contributes to ribonuclease P activity. Involved in tRNA 5'-leader removal. Located in centriolar satellite and nucleoplasm. Part of multimeric ribonuclease P complex and ribonuclease MRP complex. Biomarker of autistic disorder. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPP25NM_017793.3 linkc.196G>T p.Val66Phe missense_variant Exon 1 of 1 ENST00000322177.6 NP_060263.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPP25ENST00000322177.6 linkc.196G>T p.Val66Phe missense_variant Exon 1 of 1 6 NM_017793.3 ENSP00000317691.6 Q9BUL9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000180
AC:
4
AN:
222598
Hom.:
0
AF XY:
0.00000811
AC XY:
1
AN XY:
123262
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000894
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:
0.0000102
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000207
AC:
3
AN:
1451832
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
722358
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000451
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:
0.00
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 26, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.196G>T (p.V66F) alteration is located in exon 1 (coding exon 1) of the RPP25 gene. This alteration results from a G to T substitution at nucleotide position 196, causing the valine (V) at amino acid position 66 to be replaced by a phenylalanine (F). 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
Pathogenic
0.72
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Benign
0.33
T
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.87
D
M_CAP
Benign
0.055
D
MetaRNN
Pathogenic
0.86
D
MetaSVM
Uncertain
-0.0059
T
MutationAssessor
Pathogenic
3.0
M
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-4.3
D
REVEL
Uncertain
0.45
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0050
D
Polyphen
1.0
D
Vest4
0.73
MutPred
0.76
Loss of MoRF binding (P = 0.0806);
MVP
0.62
MPC
1.9
ClinPred
0.97
D
GERP RS
4.2
Varity_R
0.89
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1212785431; hg19: chr15-75248729; API