rs4886844

chr15-74016599-T-C

Variant summary

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

The NM_033238.3(PML):c.603-6229T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 151,750 control chromosomes in the GnomAD database, including 19,330 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 (19330 hom., cov: 31)
• Consequence: PML NM_033238.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.673

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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PML	NM_033238.3	c.603-6229T>C		intron_variant		ENST00000268058.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PML	ENST00000268058.8	c.603-6229T>C		intron_variant		1	NM_033238.3	P1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75479 AN: 151632 Hom.: 19331 Cov.: 31

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.487

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

GnomAD4 genome AF: 0.498 AC: 75521 AN: 151750 Hom.: 19330 Cov.: 31 AF XY: 0.500 AC XY: 37060 AN XY: 74164

Gnomad4 AFR AF: 0.375

Gnomad4 AMR AF: 0.517

Gnomad4 ASJ AF: 0.451

Gnomad4 EAS AF: 0.445

Gnomad4 SAS AF: 0.483

Gnomad4 FIN AF: 0.598

Gnomad4 NFE AF: 0.563

Gnomad4 OTH AF: 0.487

Alfa AF: 0.539 Hom.: 9813

Bravo AF: 0.485

Asia WGS AF: 0.451 AC: 1568 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	12
Dann	Benign	0.85

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: rs4886844; hg19: chr15-74308940;