rs869312187

Positions:

• chr19-54128351-C-A
• chr19-54128351-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_015629.4(PRPF31):​c.1120C>A​(p.Gln374Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,396,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q374Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PRPF31 NM_015629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.280585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF31	NM_015629.4	c.1120C>A	p.Gln374Lys	missense_variant	11/14	ENST00000321030.9	NP_056444.3
PRPF31	XM_006723137.5	c.1120C>A	p.Gln374Lys	missense_variant	11/14		XP_006723200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPF31	ENST00000321030.9	c.1120C>A	p.Gln374Lys	missense_variant	11/14	1	NM_015629.4	ENSP00000324122.4
PRPF31	ENST00000391755.1	c.1102C>A	p.Gln368Lys	missense_variant	10/13	5		ENSP00000375635.1
PRPF31	ENST00000419967.5	c.1120C>A	p.Gln374Lys	missense_variant	11/13	5		ENSP00000405166.2
PRPF31	ENST00000466404.5	n.1094C>A		non_coding_transcript_exon_variant	9/11	2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396210 Hom.: 0 Cov.: 43 AF XY: 0.00 AC XY: 0 AN XY: 688670

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: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PRPF31-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 374 of the PRPF31 protein (p.Gln374Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Benign	0.87
DEOGEN2	Benign	0.27	.;T;.
Eigen	Benign	0.051
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Uncertain	0.042	D
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.94	T;T;T
Sift4G	Benign	0.99	T;T;T
Polyphen		0.078	.;B;.
Vest4		0.35
MutPred		0.55		Gain of ubiquitination at Q374 (P = 0.0094);Gain of ubiquitination at Q374 (P = 0.0094);.;
MVP		0.67
MPC		1.1
ClinPred		0.71	D
GERP RS		4.5
Varity_R		0.46
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs869312187; hg19: chr19-54631726;