19-54118281-G-C

Position:

• chr19-54118281-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_015629.4(PRPF31):​c.3G>C​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRPF31 NM_015629.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.59

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-AS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_015629.4 (PRPF31) was described as [Likely_pathogenic] in ClinVar as 438044
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-54118281-G-C is Pathogenic according to our data. Variant chr19-54118281-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2818311.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPF31	NM_015629.4	c.3G>C	p.Met1?	start_lost	2/14	ENST00000321030.9
PRPF31-AS1	XR_007067340.1	n.1843-602C>G		intron_variant, non_coding_transcript_variant
PRPF31	XM_006723137.5	c.3G>C	p.Met1?	start_lost	2/14
PRPF31	XM_047438587.1	c.3G>C	p.Met1?	start_lost	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPF31	ENST00000321030.9	c.3G>C	p.Met1?	start_lost	2/14	1	NM_015629.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Disruption of the initiator codon has been observed in individuals with retinitis pigmentosa (PMID: 28041643; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the PRPF31 mRNA. The next in-frame methionine is located at codon 59. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Benign	0.026
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.0	.;B;.;.;.;.
Vest4		0.92
MutPred		0.96		Gain of catalytic residue at M1 (P = 0.0276);Gain of catalytic residue at M1 (P = 0.0276);Gain of catalytic residue at M1 (P = 0.0276);Gain of catalytic residue at M1 (P = 0.0276);Gain of catalytic residue at M1 (P = 0.0276);Gain of catalytic residue at M1 (P = 0.0276);
MVP		0.97
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 11

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-54621661;