chr1-150324880-C-CTT

Variant names:

• chr1-150324880-C-CTT
• rs75011188
• NM_004698.4:c.-48-4_-48-3dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_004698.4(PRPF3):​c.-48-4_-48-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,251,300 control chromosomes in the GnomAD database, including 2,163 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 0)
  • Exomes 𝑓: 0.13 (2162 hom.)
• Consequence: PRPF3 NM_004698.4 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.713
• Publications: 0 publications found

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]

PRPF3 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 18

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09405458 fraction of the gene. Cryptic splice site detected, with MaxEntScore 13, offset of 0 (no position change), new splice context is: tctcttttttttttttttAGgtg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004698.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPF3	NM_004698.4	MANE Select	c.-48-4_-48-3dupTT		splice_acceptor intron	N/A	NP_004689.1	O43395-1
	PRPF3	NM_001350529.1		c.-549-4_-549-3dupTT		splice_acceptor intron	N/A	NP_001337458.1
	PRPF3	NR_146766.1		n.126-4_126-3dupTT		splice_acceptor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPF3	ENST00000324862.7	TSL:1 MANE Select	c.-48-15_-48-14insTT		intron	N/A	ENSP00000315379.6	O43395-1
	PRPF3	ENST00000496202.5	TSL:1	n.115-15_115-14insTT		intron	N/A
	PRPF3	ENST00000907626.1		c.-48-15_-48-14insTT		intron	N/A	ENSP00000577685.1

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 169 AN: 144028 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000697

Gnomad ASJ AF: 0.000584

Gnomad EAS AF: 0.000792

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00681

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00114

Gnomad OTH AF: 0.00354

GnomAD4 exome AF: 0.132 AC: 146676 AN: 1107244 Hom.: 2162 Cov.: 24 AF XY: 0.134 AC XY: 74527 AN XY: 555092

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0913 AC: 2128 AN: 23312

American (AMR) AF: 0.138 AC: 3912 AN: 28446

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 2926 AN: 18702

East Asian (EAS) AF: 0.158 AC: 4808 AN: 30360

South Asian (SAS) AF: 0.144 AC: 9433 AN: 65340

European-Finnish (FIN) AF: 0.145 AC: 4998 AN: 34448

Middle Eastern (MID) AF: 0.117 AC: 389 AN: 3328

European-Non Finnish (NFE) AF: 0.130 AC: 112002 AN: 858846

Other (OTH) AF: 0.137 AC: 6080 AN: 44462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00117 AC: 169 AN: 144056 Hom.: 1 Cov.: 0 AF XY: 0.00128 AC XY: 89 AN XY: 69562

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000409 AC: 16 AN: 39126

American (AMR) AF: 0.000697 AC: 10 AN: 14356

Ashkenazi Jewish (ASJ) AF: 0.000584 AC: 2 AN: 3422

East Asian (EAS) AF: 0.000795 AC: 4 AN: 5032

South Asian (SAS) AF: 0.00 AC: 0 AN: 4616

European-Finnish (FIN) AF: 0.00681 AC: 54 AN: 7932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00114 AC: 76 AN: 66396

Other (OTH) AF: 0.00352 AC: 7 AN: 1990

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1622

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.71

Splicing

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

Other links and lift over

dbSNP: rs75011188; hg19: chr1-150297334;