rs2304717

Positions:

• chr15-74034216-T-C
• chr15-74034216-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000563500.5(PML):​c.*608T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 539,790 control chromosomes in the GnomAD database, including 75,824 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.50 (19735 hom., cov: 32)
  • Exomes 𝑓: 0.53 (56089 hom.)
• Consequence: PML ENST00000563500.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.590

Genes affected

PML (HGNC:9113): (PML nuclear body scaffold) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. This phosphoprotein localizes to nuclear bodies where it functions as a transcription factor and tumor suppressor. Its expression is cell-cycle related and it regulates the p53 response to oncogenic signals. The gene is often involved in the translocation with the retinoic acid receptor alpha gene associated with acute promyelocytic leukemia (APL). Extensive alternative splicing of this gene results in several variations of the protein's central and C-terminal regions; all variants encode the same N-terminus. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PML	NM_033238.3	c.1658-262T>C		intron_variant		ENST00000268058.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PML	ENST00000268058.8	c.1658-262T>C		intron_variant		1	NM_033238.3	P1

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76602 AN: 151980 Hom.: 19738 Cov.: 32

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.489

GnomAD4 exome AF: 0.533 AC: 206521 AN: 387692 Hom.: 56089 Cov.: 4 AF XY: 0.530 AC XY: 108464 AN XY: 204720

Gnomad4 AFR exome AF: 0.401

Gnomad4 AMR exome AF: 0.524

Gnomad4 ASJ exome AF: 0.465

Gnomad4 EAS exome AF: 0.467

Gnomad4 SAS exome AF: 0.483

Gnomad4 FIN exome AF: 0.604

Gnomad4 NFE exome AF: 0.556

Gnomad4 OTH exome AF: 0.515

GnomAD4 genome AF: 0.504 AC: 76636 AN: 152098 Hom.: 19735 Cov.: 32 AF XY: 0.505 AC XY: 37567 AN XY: 74384

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.524

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.448

Gnomad4 SAS AF: 0.484

Gnomad4 FIN AF: 0.597

Gnomad4 NFE AF: 0.563

Gnomad4 OTH AF: 0.490

Alfa AF: 0.537 Hom.: 3514

Bravo AF: 0.491

Asia WGS AF: 0.452 AC: 1572 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.69
DANN	Benign	0.53

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: rs2304717; hg19: chr15-74326557;