rs9479

Positions:

• chr15-74036235-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033239.3(PML):​c.*284A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,526,804 control chromosomes in the GnomAD database, including 192,950 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (19502 hom., cov: 31)
  • Exomes 𝑓: 0.50 (173448 hom.)
• Consequence: PML NM_033239.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.515

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 15-74036235-A-G is Benign according to our data. Variant chr15-74036235-A-G is described in ClinVar as [Benign]. Clinvar id is 1288742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PML	NM_033238.3	c.1710+1705A>G		intron_variant		ENST00000268058.8	NP_150241.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PML	ENST00000268058.8	c.1710+1705A>G		intron_variant		1	NM_033238.3	ENSP00000268058.3

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76655 AN: 151700 Hom.: 19493 Cov.: 31

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.515

GnomAD4 exome AF: 0.501 AC: 688672 AN: 1374986 Hom.: 173448 Cov.: 51 AF XY: 0.502 AC XY: 340204 AN XY: 677800

Gnomad4 AFR exome AF: 0.473

Gnomad4 AMR exome AF: 0.512

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.652

Gnomad4 SAS exome AF: 0.525

Gnomad4 FIN exome AF: 0.563

Gnomad4 NFE exome AF: 0.493

Gnomad4 OTH exome AF: 0.502

GnomAD4 genome AF: 0.505 AC: 76715 AN: 151818 Hom.: 19502 Cov.: 31 AF XY: 0.509 AC XY: 37749 AN XY: 74188

Gnomad4 AFR AF: 0.473

Gnomad4 AMR AF: 0.532

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.636

Gnomad4 SAS AF: 0.527

Gnomad4 FIN AF: 0.561

Gnomad4 NFE AF: 0.502

Gnomad4 OTH AF: 0.517

Alfa AF: 0.498 Hom.: 10325

Bravo AF: 0.497

Asia WGS AF: 0.596 AC: 2070 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 24886876) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.73
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

Other links and lift over

dbSNP: rs9479; hg19: chr15-74328576; COSMIC: COSV51446452; COSMIC: COSV51446452;