Genetic Variant PRPF6:c.-25C>T (chr20-63981221-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012469.4(PRPF6):c.-25C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0463 in 1,592,058 control chromosomes in the GnomAD database, including 2,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 129 hom., cov: 33)

Exomes 𝑓: 0.048 ( 1911 hom. )

Consequence

PRPF6
NM_012469.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.143

Variant links:

Genes affected

PRPF6 (HGNC:15860): (pre-mRNA processing factor 6) The protein encoded by this gene appears to be involved in pre-mRNA splicing, possibly acting as a bridging factor between U5 and U4/U6 snRNPs in formation of the spliceosome. The encoded protein also can bind androgen receptor, providing a link between transcriptional activation and splicing. [provided by RefSeq, Jul 2008]

PRPF6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 20-63981221-C-T is Benign according to our data. Variant chr20-63981221-C-T is described in ClinVar as [Benign]. Clinvar id is 339460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PRPF6	NM_012469.4 link	c.-25C>T	5_prime_UTR_variant	Exon 1 of 21	ENST00000266079.5	NP_036601.2	O94906-1
PRPF6	XM_006723769.4 link	c.-25C>T	5_prime_UTR_variant	Exon 1 of 20		XP_006723832.1
PRPF6	XR_007067448.1 link	n.90C>T	non_coding_transcript_exon_variant	Exon 1 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPF6	ENST00000266079 link	c.-25C>T		5_prime_UTR_variant	Exon 1 of 21	1	NM_012469.4	ENSP00000266079.4		O94906-1

Frequencies

GnomAD3 genomes

AF:

0.0319

AC:

4856

AN:

152250

Hom.:

129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00859

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0211

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0184

Gnomad FIN

AF:

0.0254

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0534

Gnomad OTH

AF:

0.0296

GnomAD3 exomes

AF:

0.0317

AC:

6777

AN:

213972

Hom.:

132

AF XY:

0.0330

AC XY:

3809

AN XY:

115298

show subpopulations

Gnomad AFR exome

AF:

0.00825

Gnomad AMR exome

AF:

0.0146

Gnomad ASJ exome

AF:

0.0243

Gnomad EAS exome

AF:

0.0000617

Gnomad SAS exome

AF:

0.0220

Gnomad FIN exome

AF:

0.0286

Gnomad NFE exome

AF:

0.0500

Gnomad OTH exome

AF:

0.0310

GnomAD4 exome

AF:

0.0478

AC:

68881

AN:

1439690

Hom.:

1911

Cov.:

AF XY:

0.0475

AC XY:

33927

AN XY:

714150

show subpopulations

Gnomad4 AFR exome

AF:

0.00649

Gnomad4 AMR exome

AF:

0.0148

Gnomad4 ASJ exome

AF:

0.0244

Gnomad4 EAS exome

AF:

0.000154

Gnomad4 SAS exome

AF:

0.0233

Gnomad4 FIN exome

AF:

0.0316

Gnomad4 NFE exome

AF:

0.0555

Gnomad4 OTH exome

AF:

0.0433

GnomAD4 genome

AF:

0.0319

AC:

4855

AN:

152368

Hom.:

129

Cov.:

AF XY:

0.0303

AC XY:

2256

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00856

Gnomad4 AMR

AF:

0.0210

Gnomad4 ASJ

AF:

0.0225

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0184

Gnomad4 FIN

AF:

0.0254

Gnomad4 NFE

AF:

0.0534

Gnomad4 OTH

AF:

0.0293

Alfa

AF:

0.0452

Hom.:

Bravo

AF:

0.0311

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Retinitis pigmentosa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

7.7

DANN

Benign

0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over