19-54118281-G-A

Position:

• chr19-54118281-G-A

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>A​(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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRPF31 NM_015629.4 start_lost
• Clinical Significance: Likely 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]

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 Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-54118281-G-A is Pathogenic according to our data. Variant chr19-54118281-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 804151.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-54118281-G-A is described in Lovd as [Likely_pathogenic]. Variant chr19-54118281-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF31	NM_015629.4	c.3G>A	p.Met1?	start_lost	2/14	ENST00000321030.9	NP_056444.3
PRPF31	XM_006723137.5	c.3G>A	p.Met1?	start_lost	2/14		XP_006723200.1
PRPF31	XM_047438587.1	c.3G>A	p.Met1?	start_lost	2/10		XP_047294543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPF31	ENST00000321030.9	c.3G>A	p.Met1?	start_lost	2/14	1	NM_015629.4	ENSP00000324122.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	.;D;T;.;T;.
Eigen	Benign	0.026
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;.;D;D;D;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)		0.030		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

Other links and lift over

dbSNP: rs1600324262; hg19: chr19-54621661;