1-150324893-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PVS1_Moderate PP3_Strong BS2

The NM_004698.4(PRPF3):c.-48-2A>T variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0067 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRPF3 NM_004698.4 splice_acceptor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

Genes affected

PRPF3 (HGNC:17348): (pre-mRNA processing factor 3) The removal of introns from nuclear pre-mRNAs occurs on complexes called spliceosomes, which are made up of 4 small nuclear ribonucleoprotein (snRNP) particles and an undefined number of transiently associated splicing factors. This gene product is one of several proteins that associate with U4 and U6 snRNPs. Mutations in this gene are associated with retinitis pigmentosa-18. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.09356725 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.9, offset of 6, new splice context is: tttttttttttttggtgtAGtat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High AC in GnomAdExome at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPF3	NM_004698.4	c.-48-2A>T		splice_acceptor_variant		ENST00000324862.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPF3	ENST00000324862.7	c.-48-2A>T		splice_acceptor_variant		1	NM_004698.4	P1
PRPF3	ENST00000496202.5	n.115-2A>T		splice_acceptor_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 24 AN: 25380 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.000600

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000337

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00216

Gnomad SAS AF: 0.00243

Gnomad FIN AF: 0.00212

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000103 AC: 14 AN: 135700 Hom.: 0 AF XY: 0.0000658 AC XY: 5 AN XY: 76004

Gnomad AFR exome AF: 0.000358

Gnomad AMR exome AF: 0.0000631

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000214

Gnomad SAS exome AF: 0.0000626

Gnomad FIN exome AF: 0.0000857

Gnomad NFE exome AF: 0.0000908

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00669 AC: 3309 AN: 494490 Hom.: 1 Cov.: 19 AF XY: 0.00630 AC XY: 1586 AN XY: 251626

Gnomad4 AFR exome AF: 0.00402

Gnomad4 AMR exome AF: 0.0161

Gnomad4 ASJ exome AF: 0.00462

Gnomad4 EAS exome AF: 0.00311

Gnomad4 SAS exome AF: 0.00244

Gnomad4 FIN exome AF: 0.0637

Gnomad4 NFE exome AF: 0.00465

Gnomad4 OTH exome AF: 0.00520

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000945 AC: 24 AN: 25394 Hom.: 0 Cov.: 0 AF XY: 0.00110 AC XY: 14 AN XY: 12682

Gnomad4 AFR AF: 0.000598

Gnomad4 AMR AF: 0.000337

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00216

Gnomad4 SAS AF: 0.00245

Gnomad4 FIN AF: 0.00212

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000736 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa 18 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	27
Dann	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.95		Position offset: 8
DS_AL_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782747350; hg19: chr1-150297351; COSMIC: COSV105203402; COSMIC: COSV105203402;