Variant 9-113275747-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001244926.2(PRPF4):c.4G>A(p.Ala2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PRPF4
NM_001244926.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.01

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]

PRPF4 links:

PRPF4 (HGNC:):

PRPF4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2817887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF4	NM_001244926.2 linkuse as main transcript	c.4G>A	p.Ala2Thr	missense_variant	1/14	ENST00000374198.5	NP_001231855.1	O43172-2Q5T1M7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPF4	ENST00000374198.5 linkuse as main transcript	c.4G>A	p.Ala2Thr	missense_variant	1/14	1	NM_001244926.2	ENSP00000363313.4		O43172-2
PRPF4	ENST00000374199.9 linkuse as main transcript	c.4G>A	p.Ala2Thr	missense_variant	1/14	1		ENSP00000363315.4		O43172-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247284

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134144

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:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459666

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726218

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 03, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PRPF4-related conditions. This variant is present in population databases (rs748886389, ExAC 0.006%). This sequence change replaces alanine with threonine at codon 2 of the PRPF4 protein (p.Ala2Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

.;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.0

N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.42

N;N

REVEL

Benign

0.24

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.24

T;D

Polyphen

0.049

.;B

Vest4

0.36

MutPred

0.15

Gain of glycosylation at A2 (P = 0.0105);Gain of glycosylation at A2 (P = 0.0105);

MVP

0.84

MPC

0.61

ClinPred

0.64

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.21

gMVP

0.54

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over