NM_012469.4:c.2185C>T

Variant names:

• chr20-64027138-C-T
• rs387907100
• NM_012469.4:c.2185C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_012469.4(PRPF6):​c.2185C>T​(p.Arg729Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R729Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: PRPF6 NM_012469.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.00
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 60

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012469.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPF6	NM_012469.4	MANE Select	c.2185C>T	p.Arg729Trp	missense	Exon 16 of 21	NP_036601.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPF6	ENST00000266079.5	TSL:1 MANE Select	c.2185C>T	p.Arg729Trp	missense	Exon 16 of 21	ENSP00000266079.4	O94906-1
	PRPF6	ENST00000961103.1		c.2251C>T	p.Arg751Trp	missense	Exon 17 of 22	ENSP00000631162.1
	PRPF6	ENST00000855544.1		c.2212C>T	p.Arg738Trp	missense	Exon 17 of 22	ENSP00000525603.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250372 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000890 AC: 13 AN: 1461402 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 726992

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5514

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
1	-	-	Retinitis pigmentosa 60 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		3.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.46		Loss of disorder (P = 0.0067)
MVP		0.89
MPC		1.4
ClinPred		0.97	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.93
Mutation Taster		=18/82	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: rs387907100; hg19: chr20-62658491; COSMIC: COSV53868700;