9-113275672-C-T

Variant names:

• chr9-113275672-C-T
• rs377499486
• NM_001244926.2:c.-72C>T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001244926.2(PRPF4):​c.-72C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,550,452 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (1 hom.)
• Consequence: PRPF4 NM_001244926.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.30

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 9-113275672-C-T is Benign according to our data. Variant chr9-113275672-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3042380.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 166 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPF4	NM_001244926.2	c.-72C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 14	ENST00000374198.5	NP_001231855.1
PRPF4	NM_001244926.2	c.-72C>T		5_prime_UTR_variant	Exon 1 of 14	ENST00000374198.5	NP_001231855.1
CDC26	NM_139286.4	c.-442G>A		upstream_gene_variant		ENST00000374206.4	NP_644815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPF4	ENST00000374198	c.-72C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 14	1	NM_001244926.2	ENSP00000363313.4
PRPF4	ENST00000374198	c.-72C>T		5_prime_UTR_variant	Exon 1 of 14	1	NM_001244926.2	ENSP00000363313.4
CDC26	ENST00000374206.4	c.-442G>A		upstream_gene_variant		1	NM_139286.4	ENSP00000363322.3

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

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: 0.00179

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00166 AC: 2322 AN: 1398128 Hom.: 1 Cov.: 26 AF XY: 0.00154 AC XY: 1068 AN XY: 692342

Gnomad4 AFR exome AF: 0.000319

Gnomad4 AMR exome AF: 0.00160

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000373

Gnomad4 FIN exome AF: 0.0000403

Gnomad4 NFE exome AF: 0.00198

Gnomad4 OTH exome AF: 0.00203

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.000993 AC XY: 74 AN XY: 74492

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.00236

Bravo AF: 0.00121

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PRPF4-related disorder Benign:1

Apr 02, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	11
DANN	Benign	0.87

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

Other links and lift over

dbSNP: rs377499486; hg19: chr9-116037952; COSMIC: COSV104684050; COSMIC: COSV104684050;