chr19-54121895-G-A

Position:

• chr19-54121895-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_015629.4(PRPF31):​c.274G>A​(p.Val92Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000274 in 1,460,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: PRPF31 NM_015629.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.23

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_benign. Variant got -5 ACMG points.

• 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=0.22962534).
• BS2: High AC in GnomAdExome4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF31	NM_015629.4	c.274G>A	p.Val92Ile	missense_variant	4/14	ENST00000321030.9	NP_056444.3
PRPF31-AS1	XR_007067340.1	n.1783C>T		non_coding_transcript_exon_variant	2/3
PRPF31	XM_006723137.5	c.274G>A	p.Val92Ile	missense_variant	4/14		XP_006723200.1
PRPF31	XM_047438587.1	c.274G>A	p.Val92Ile	missense_variant	4/10		XP_047294543.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPF31	ENST00000321030.9	c.274G>A	p.Val92Ile	missense_variant	4/14	1	NM_015629.4	ENSP00000324122	P1
PRPF31-AS1	ENST00000452097.1	n.3217C>T		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000283 AC: 7 AN: 247040 Hom.: 0 AF XY: 0.0000374 AC XY: 5 AN XY: 133844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1460468 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 726356

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000814

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2024

The c.274G>A (p.V92I) alteration is located in exon 4 (coding exon 3) of the PRPF31 gene. This alteration results from a G to A substitution at nucleotide position 274, causing the valine (V) at amino acid position 92 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 24, 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. ClinVar contains an entry for this variant (Variation ID: 1427971). This variant has not been reported in the literature in individuals affected with PRPF31-related conditions. This variant is present in population databases (rs776730311, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 92 of the PRPF31 protein (p.Val92Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	.;T;T;.;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;.;D;D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.23	T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.46	N;N;.;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.71	N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D
Polyphen		0.14	.;B;.;.;.;.
Vest4		0.34
MVP		0.55
MPC		0.72
ClinPred		0.094	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.60

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: rs776730311; hg19: chr19-54625274; COSMIC: COSV58086248; COSMIC: COSV58086248;