9-113275765-T-C

Variant names:

• chr9-113275765-T-C
• NM_001244926.2:c.22T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001244926.2(PRPF4):​c.22T>C​(p.Ser8Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: PRPF4 NM_001244926.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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]

ACMG classification

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=0.22954875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPF4	NM_001244926.2	c.22T>C	p.Ser8Pro	missense_variant	Exon 1 of 14	ENST00000374198.5	NP_001231855.1
CDC26	NM_139286.4	c.-535A>G		upstream_gene_variant		ENST00000374206.4	NP_644815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPF4	ENST00000374198.5	c.22T>C	p.Ser8Pro	missense_variant	Exon 1 of 14	1	NM_001244926.2	ENSP00000363313.4
PRPF4	ENST00000374199.9	c.22T>C	p.Ser8Pro	missense_variant	Exon 1 of 14	1		ENSP00000363315.4
CDC26	ENST00000374206.4	c.-535A>G		upstream_gene_variant		1	NM_139286.4	ENSP00000363322.3
CDC26	ENST00000490408.5	n.-216A>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 8 of the PRPF4 protein (p.Ser8Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRPF4-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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	0.071
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	.;T
Eigen	Benign	-0.060
Eigen_PC	Benign	-0.0052
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.29
Sift	Uncertain	0.021	D;D
Sift4G	Benign	0.37	T;T
Polyphen		0.68	.;P
Vest4		0.27
MutPred		0.12		Loss of phosphorylation at S8 (P = 0.0186);Loss of phosphorylation at S8 (P = 0.0186);
MVP		0.84
MPC		0.79
ClinPred		0.65	D
GERP RS		2.9
Varity_R		0.21
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-116038045;