NM_015225.3:c.3011C>T

Variant names:

• chr9-76709263-G-A
• rs530978
• NM_015225.3:c.3011C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015225.3(PRUNE2):​c.3011C>T​(p.Thr1004Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,612,692 control chromosomes in the GnomAD database, including 264,258 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (20350 hom., cov: 31)
  • Exomes 𝑓: 0.57 (243908 hom.)
• Consequence: PRUNE2 NM_015225.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.258
• Publications: 23 publications found

Genes affected

PRUNE2 (HGNC:25209): (prune homolog 2 with BCH domain) The protein encoded by this gene belongs to the B-cell CLL/lymphoma 2 and adenovirus E1B 19 kDa interacting family, whose members play roles in many cellular processes including apotosis, cell transformation, and synaptic function. Several functions for this protein have been demonstrated including suppression of Ras homolog family member A activity, which results in reduced stress fiber formation and suppression of oncogenic cellular transformation. A high molecular weight isoform of this protein has also been shown to colocalize with Adaptor protein complex 2, beta-Adaptin and endodermal markers, suggesting an involvement in post-endocytic trafficking. In prostate cancer cells, this gene acts as a tumor suppressor and its expression is regulated by prostate cancer antigen 3, a non-protein coding gene on the opposite DNA strand in an intron of this gene. Prostate cancer antigen 3 regulates levels of this gene through formation of a double-stranded RNA that undergoes adenosine deaminase actin on RNA-dependent adenosine-to-inosine RNA editing. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

PCA3 (HGNC:8637): (prostate cancer associated 3) This gene produces a spliced, long non-coding RNA that is highly overexpressed in most types of prostate cancer cells and is used as a specific biomarker for this type of cancer. This gene is embedded in an intronic region of the prune2 gene on the opposite DNA strand. The transcript regulates prune2 levels through formation of a double-stranded RNA that undergoes adenosine deaminase acting on RNA-dependent adenosine-to-inosine RNA editing. In prostate cancer derived cells, overexpression of PCA induced downregulation of prune2, leading to decreased cell proliferation. Conversely, silencing in prostate cancer cells resulted in increased proliferation. Regulation of this gene appears to be sensitive to androgen-receptor activation, a molecular signature of prostate cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2017]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0055432E-5).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015225.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRUNE2	NM_015225.3	MANE Select	c.3011C>T	p.Thr1004Met	missense	Exon 8 of 19	NP_056040.2
	PRUNE2	NM_001308048.2		c.3011C>T	p.Thr1004Met	missense	Exon 8 of 18	NP_001294977.1
	PRUNE2	NM_001308047.2		c.3011C>T	p.Thr1004Met	missense	Exon 8 of 18	NP_001294976.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRUNE2	ENST00000376718.8	TSL:5 MANE Select	c.3011C>T	p.Thr1004Met	missense	Exon 8 of 19	ENSP00000365908.3
	PRUNE2	ENST00000443509.6	TSL:5	c.3011C>T	p.Thr1004Met	missense	Exon 8 of 18	ENSP00000393843.3
	PRUNE2	ENST00000428286.5	TSL:5	c.1934C>T	p.Thr645Met	missense	Exon 8 of 19	ENSP00000397425.1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74880 AN: 151856 Hom.: 20352 Cov.: 31

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.697

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.574

GnomAD2 exomes AF: 0.562 AC: 139824 AN: 248656 AF XY: 0.567

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.693

Gnomad ASJ exome AF: 0.697

Gnomad EAS exome AF: 0.370

Gnomad FIN exome AF: 0.513

Gnomad NFE exome AF: 0.599

Gnomad OTH exome AF: 0.598

GnomAD4 exome AF: 0.573 AC: 837139 AN: 1460718 Hom.: 243908 Cov.: 56 AF XY: 0.574 AC XY: 417060 AN XY: 726722

African (AFR) AF: 0.247 AC: 8274 AN: 33466

American (AMR) AF: 0.682 AC: 30507 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 18165 AN: 26128

East Asian (EAS) AF: 0.379 AC: 15031 AN: 39696

South Asian (SAS) AF: 0.539 AC: 46445 AN: 86242

European-Finnish (FIN) AF: 0.515 AC: 27518 AN: 53400

Middle Eastern (MID) AF: 0.708 AC: 4084 AN: 5768

European-Non Finnish (NFE) AF: 0.588 AC: 652887 AN: 1110952

Other (OTH) AF: 0.567 AC: 34228 AN: 60342

GnomAD4 genome AF: 0.493 AC: 74893 AN: 151974 Hom.: 20350 Cov.: 31 AF XY: 0.493 AC XY: 36571 AN XY: 74240

African (AFR) AF: 0.260 AC: 10780 AN: 41456

American (AMR) AF: 0.633 AC: 9669 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2451 AN: 3472

East Asian (EAS) AF: 0.369 AC: 1907 AN: 5170

South Asian (SAS) AF: 0.531 AC: 2556 AN: 4810

European-Finnish (FIN) AF: 0.518 AC: 5447 AN: 10524

Middle Eastern (MID) AF: 0.692 AC: 202 AN: 292

European-Non Finnish (NFE) AF: 0.593 AC: 40309 AN: 67952

Other (OTH) AF: 0.573 AC: 1207 AN: 2108

Alfa AF: 0.568 Hom.: 104359

Bravo AF: 0.490

ESP6500AA AF: 0.272 AC: 854

ESP6500EA AF: 0.605 AC: 4335

ExAC AF: 0.552 AC: 66480

Asia WGS AF: 0.434 AC: 1508 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.000010	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.26
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.099
Sift	Benign	0.31	T
Sift4G	Benign	0.22	T
Polyphen		0.94	P
Vest4		0.089
MPC		0.27
ClinPred		0.025	T
GERP RS		3.0
Varity_R		0.019
gMVP		0.10
Mutation Taster		=97/3	polymorphism (auto)

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: rs530978; hg19: chr9-79324179; COSMIC: COSV65038633;