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rs1555791188

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP3PP5

The NM_015629.4(PRPF31):​c.1A>T​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRPF31
NM_015629.4 start_lost

Scores

8
3
3

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.01
Variant links:
Genes affected
PRPF31 (HGNC:15446): (pre-mRNA processing factor 31) This gene encodes a component of the spliceosome complex and is one of several retinitis pigmentosa-causing genes. When the gene product is added to the spliceosome complex, activation occurs.[provided by RefSeq, Jan 2009]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Start lost variant, no new inframe start found.
PS1
?
    PS1 - Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
Another start lost variant in NM_015629.4 (PRPF31) was described as [Likely_pathogenic] in ClinVar as 804151
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-54118279-A-T is Pathogenic according to our data. Variant chr19-54118279-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438044.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-54118279-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRPF31NM_015629.4 linkuse as main transcriptc.1A>T p.Met1? start_lost 2/14 ENST00000321030.9
PRPF31-AS1XR_007067340.1 linkuse as main transcriptn.1843-600T>A intron_variant, non_coding_transcript_variant
PRPF31XM_006723137.5 linkuse as main transcriptc.1A>T p.Met1? start_lost 2/14
PRPF31XM_047438587.1 linkuse as main transcriptc.1A>T p.Met1? start_lost 2/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRPF31ENST00000321030.9 linkuse as main transcriptc.1A>T p.Met1? start_lost 2/141 NM_015629.4 P1Q8WWY3-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460676
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726646
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
29
DANN
Benign
0.93
Eigen
Benign
0.075
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Uncertain
0.093
D
MutationTaster
Benign
1.0
D;D;D
PROVEAN
Uncertain
-2.6
D;D;D;D;D;D
REVEL
Pathogenic
0.77
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
0.0010
.;B;.;.;.;.
Vest4
0.91
MutPred
0.93
Loss of solvent accessibility (P = 0.5485);Loss of solvent accessibility (P = 0.5485);Loss of solvent accessibility (P = 0.5485);Loss of solvent accessibility (P = 0.5485);Loss of solvent accessibility (P = 0.5485);Loss of solvent accessibility (P = 0.5485);
MVP
0.98
ClinPred
0.98
D
GERP RS
4.8
Varity_R
0.85
gMVP
0.20

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.52
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.52
Position offset: 13

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.

Other links and lift over

dbSNP: rs1555791188; hg19: chr19-54621659; API