chr9-113275760-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001244926.2(PRPF4):​c.17C>T​(p.Ala6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A6A) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PRPF4
NM_001244926.2 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.22
Variant links:
Genes affected
PRPF4 (HGNC:17349): (pre-mRNA splicing tri-snRNP complex factor PRPF4) The protein encoded by this gene is part of a heteromeric complex that binds U4, U5, and U6 small nuclear RNAs and is involved in pre-mRNA splicing. The encoded protein also is a mitotic checkpoint protein and a regulator of chemoresistance in human ovarian cancer. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2016]
CDC26 (HGNC:17839): (cell division cycle 26) The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Cdc26, a component of cell cycle anaphase-promoting complex (APC). APC is composed of a group of highly conserved proteins and functions as a cell cycle-regulated ubiquitin-protein ligase. APC thus is responsible for the cell cycle regulated proteolysis of various proteins. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11541799).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRPF4NM_001244926.2 linkc.17C>T p.Ala6Val missense_variant Exon 1 of 14 ENST00000374198.5 NP_001231855.1 O43172-2Q5T1M7
CDC26NM_139286.4 linkc.-530G>A upstream_gene_variant ENST00000374206.4 NP_644815.1 Q8NHZ8A0A024R832

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRPF4ENST00000374198.5 linkc.17C>T p.Ala6Val missense_variant Exon 1 of 14 1 NM_001244926.2 ENSP00000363313.4 O43172-2
PRPF4ENST00000374199.9 linkc.17C>T p.Ala6Val missense_variant Exon 1 of 14 1 ENSP00000363315.4 O43172-1
CDC26ENST00000374206.4 linkc.-530G>A upstream_gene_variant 1 NM_139286.4 ENSP00000363322.3 Q8NHZ8
CDC26ENST00000490408.5 linkn.-211G>A upstream_gene_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1460336
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726510
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Mar 16, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 6 of the PRPF4 protein (p.Ala6Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PRPF4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.018
.;T
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.14
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.65
T;T
M_CAP
Benign
0.0092
T
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.69
N;N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.20
N;N
REVEL
Benign
0.083
Sift
Benign
0.055
T;T
Sift4G
Benign
0.25
T;T
Polyphen
0.015
.;B
Vest4
0.14
MutPred
0.23
Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);
MVP
0.35
MPC
0.63
ClinPred
0.53
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.11
gMVP
0.48

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: rs1200954096; hg19: chr9-116038040; API