chr17-1653558-G-A

Variant names:

• chr17-1653558-G-A
• rs387906971
• NM_006445.4:c.6353C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_006445.4(PRPF8):​c.6353C>T​(p.Ser2118Phe) variant causes a missense 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2118P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRPF8 NM_006445.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.76
• Publications: 8 publications found

Genes affected

PRPF8 (HGNC:17340): (pre-mRNA processing factor 8) Pre-mRNA splicing occurs in 2 sequential transesterification steps. The protein encoded by this gene is a component of both U2- and U12-dependent spliceosomes, and found to be essential for the catalytic step II in pre-mRNA splicing process. It contains several WD repeats, which function in protein-protein interactions. This protein has a sequence similarity to yeast Prp8 protein. This gene is a candidate gene for autosomal dominant retinitis pigmentosa. [provided by RefSeq, Jul 2008]

PRPF8 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glaucoma

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PRPF8 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 8.2838 (above the threshold of 3.09). Trascript score misZ: 11.324 (above the threshold of 3.09). GenCC associations: The gene is linked to retinitis pigmentosa 13, retinitis pigmentosa, neurodevelopmental disorder, glaucoma, inherited retinal dystrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• PP5: Variant 17-1653558-G-A is Pathogenic according to our data. Variant chr17-1653558-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30666.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPF8	NM_006445.4	c.6353C>T	p.Ser2118Phe	missense_variant	Exon 39 of 43	ENST00000304992.11	NP_006436.3
PRPF8	XM_024450537.2	c.6353C>T	p.Ser2118Phe	missense_variant	Exon 39 of 43		XP_024306305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPF8	ENST00000304992.11	c.6353C>T	p.Ser2118Phe	missense_variant	Exon 39 of 43	1	NM_006445.4	ENSP00000304350.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinitis pigmentosa 13 Pathogenic:1

Dec 02, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	3.7	H;H
PhyloP100		9.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.1	D;.
REVEL	Uncertain	0.47
Sift	Benign	0.072	T;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.98	D;D
Vest4		0.87
MutPred		0.72		Loss of catalytic residue at S2118 (P = 0.0665);Loss of catalytic residue at S2118 (P = 0.0665);
MVP		0.80
MPC		2.7
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.88
gMVP		0.98
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906971; hg19: chr17-1556852;