Genetic Variant PRPF31:p.Met1? (chr19-54118279-A-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP3PP5

The NM_015629.4(PRPF31):c.1A>T(p.Met1?) variant causes a initiator codon 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 initiator_codon

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.01

Publications

0 publications found

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]

PRPF31 Gene-Disease associations (from GenCC):

PRPF31-related retinopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa 11
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PRPF31 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 20 pathogenic variants. Next in-frame start position is after 59 codons. Genomic position: 54118453. Lost 0.117 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 19-54118279-A-T is Pathogenic according to our data. Variant chr19-54118279-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438044.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPF31	NM_015629.4 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 14	ENST00000321030.9	NP_056444.3	Q8WWY3-1
PRPF31	XM_006723137.5 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 14		XP_006723200.1	Q8WWY3-1
PRPF31	XM_047438587.1 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 10		XP_047294543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPF31	ENST00000321030.9 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 14	1	NM_015629.4	ENSP00000324122.4		Q8WWY3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460676

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726646

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4852

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111962

Other (OTH)

AF:

0.00

AC:

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Retinitis pigmentosa

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.51

.;D;T;.;T;.

Eigen

Benign

0.075

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

.;.;D;D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Uncertain

0.093

PhyloP100

8.0

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

GERP RS

4.8

PromoterAI

0.030

Neutral

(source)

Varity_R

0.85

gMVP

0.20

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over