19-54123867-G-C

Position:

• chr19-54123867-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The ENST00000321030.9(PRPF31):​c.646G>C​(p.Ala216Pro) variant causes a missense change. 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRPF31 ENST00000321030.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.86

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:40700): (PRPF31 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain Nop (size 118) in uniprot entity PRP31_HUMAN there are 30 pathogenic changes around while only 1 benign (97%) in ENST00000321030.9
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 19-54123867-G-C is Pathogenic according to our data. Variant chr19-54123867-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 4359.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-54123867-G-C is described in UniProt as null. Variant chr19-54123867-G-C is described in UniProt as null. Variant chr19-54123867-G-C is described in UniProt as null. Variant chr19-54123867-G-C is described in UniProt as null. Variant chr19-54123867-G-C is described in UniProt as null. Variant chr19-54123867-G-C is described in UniProt as null. Variant chr19-54123867-G-C is described in UniProt as null. Variant chr19-54123867-G-C is described in UniProt as null. Variant chr19-54123867-G-C is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF31	NM_015629.4	c.646G>C	p.Ala216Pro	missense_variant	7/14	ENST00000321030.9	NP_056444.3
PRPF31-AS1	XR_007067340.1	n.88-277C>G		intron_variant, non_coding_transcript_variant
PRPF31	XM_006723137.5	c.646G>C	p.Ala216Pro	missense_variant	7/14		XP_006723200.1
PRPF31	XM_047438587.1	c.646G>C	p.Ala216Pro	missense_variant	7/10		XP_047294543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPF31	ENST00000321030.9	c.646G>C	p.Ala216Pro	missense_variant	7/14	1	NM_015629.4	ENSP00000324122	P1
PRPF31-AS1	ENST00000452097.1	n.1477C>G		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinitis pigmentosa 11 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D;T;.;T;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;.;D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.3	H;H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.
Vest4		0.96
MutPred		0.98		Gain of catalytic residue at A216 (P = 0.0357);Gain of catalytic residue at A216 (P = 0.0357);Gain of catalytic residue at A216 (P = 0.0357);Gain of catalytic residue at A216 (P = 0.0357);Gain of catalytic residue at A216 (P = 0.0357);Gain of catalytic residue at A216 (P = 0.0357);
MVP		0.86
MPC		2.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs119475042; hg19: chr19-54627246;