chr19-54121892-C-T

Position:

chr19-54121892-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1PP2BP4_ModerateBS1_SupportingBS2

The ENST00000321030.9(PRPF31):c.271C>T(p.Arg91Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,612,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R91H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

PRPF31
ENST00000321030.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.90

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 links:

PRPF31-AS1 (HGNC:40700): (PRPF31 antisense RNA 1)

PRPF31-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a coiled_coil_region (size 35) in uniprot entity PRP31_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in ENST00000321030.9

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PRPF31. . Gene score misZ 3.0492 (greater than the threshold 3.09). Trascript score misZ 3.3753 (greater than threshold 3.09). GenCC has associacion of gene with retinitis pigmentosa 11, PRPF31-related retinopathy, retinitis pigmentosa.

BP4

Computational evidence support a benign effect (MetaRNN=0.19194975).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000092 (14/152218) while in subpopulation SAS AF= 0.000207 (1/4834). AF 95% confidence interval is 0.000102. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PRPF31	NM_015629.4 linkuse as main transcript	c.271C>T	p.Arg91Cys	missense_variant	4/14	ENST00000321030.9	NP_056444.3
PRPF31-AS1	XR_007067340.1 linkuse as main transcript	n.1786G>A		non_coding_transcript_exon_variant	2/3
PRPF31	XM_006723137.5 linkuse as main transcript	c.271C>T	p.Arg91Cys	missense_variant	4/14		XP_006723200.1
PRPF31	XM_047438587.1 linkuse as main transcript	c.271C>T	p.Arg91Cys	missense_variant	4/10		XP_047294543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPF31	ENST00000321030.9 linkuse as main transcript	c.271C>T	p.Arg91Cys	missense_variant	4/14	1	NM_015629.4	ENSP00000324122	P1	Q8WWY3-1
PRPF31-AS1	ENST00000452097.1 linkuse as main transcript	n.3220G>A		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000130

AC:

AN:

246748

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

133704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000197

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000164

AC:

239

AN:

1460374

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

726306

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000195

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000181

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.271C>T (p.R91C) alteration is located in exon 4 (coding exon 3) of the PRPF31 gene. This alteration results from a C to T substitution at nucleotide position 271, causing the arginine (R) at amino acid position 91 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 03, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 91 of the PRPF31 protein (p.Arg91Cys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1508982). This variant has not been reported in the literature in individuals affected with PRPF31-related conditions. This variant is present in population databases (rs376072327, gnomAD 0.02%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.47

.;T;T;.;T;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

.;.;D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.19

T;T;T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.55

N;N;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D

REVEL

Uncertain

0.44

Sift

Benign

0.13

T;T;T;T;T;T

Sift4G

Uncertain

0.058

T;T;T;T;T;T

Polyphen

0.0040

.;B;.;.;.;.

Vest4

0.78

MVP

0.93

MPC

1.1

ClinPred

0.077

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over