rs8039584

Positions:

• chr15-74013625-C-T

Variant summary

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

The NM_033238.3(PML):​c.603-9203C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0501 in 152,258 control chromosomes in the GnomAD database, including 250 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 0.050 (250 hom., cov: 32)
• Consequence: PML NM_033238.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.273

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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PML	NM_033238.3	c.603-9203C>T		intron_variant		ENST00000268058.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PML	ENST00000268058.8	c.603-9203C>T		intron_variant		1	NM_033238.3	P1

Frequencies

GnomAD3 genomes AF: 0.0500 AC: 7609 AN: 152140 Hom.: 247 Cov.: 32

Gnomad AFR AF: 0.0897

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0614

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0474

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0385

Gnomad OTH AF: 0.0445

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0501 AC: 7632 AN: 152258 Hom.: 250 Cov.: 32 AF XY: 0.0491 AC XY: 3652 AN XY: 74448

Gnomad4 AFR AF: 0.0900

Gnomad4 AMR AF: 0.0267

Gnomad4 ASJ AF: 0.0614

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00788

Gnomad4 FIN AF: 0.0474

Gnomad4 NFE AF: 0.0385

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0399 Hom.: 60

Bravo AF: 0.0505

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.35

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: rs8039584; hg19: chr15-74305966;