rs119475042

chr19-54123867-G-Achr19-54123867-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM5 PP2 PP3_Moderate

The NM_015629.4(PRPF31):c.646G>A(p.Ala216Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A216P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PRPF31 NM_015629.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Likely_pathogenic. Variant got 7 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 NM_015629.4
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP2: Missense variant where missense usually causes diseases, PRPF31
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPF31	NM_015629.4	c.646G>A	p.Ala216Thr	missense_variant	7/14	ENST00000321030.9
PRPF31-AS1	XR_007067340.1	n.88-277C>T		intron_variant, non_coding_transcript_variant
PRPF31	XM_006723137.5	c.646G>A	p.Ala216Thr	missense_variant	7/14
PRPF31	XM_047438587.1	c.646G>A	p.Ala216Thr	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPF31	ENST00000321030.9	c.646G>A	p.Ala216Thr	missense_variant	7/14	1	NM_015629.4	P1
PRPF31-AS1	ENST00000452097.1	n.1477C>T		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251258 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135808

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461640 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.9	H;H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D
REVEL	Pathogenic	0.79
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		0.92
MVP		0.75
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.86
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV58084924;