NM_033238.3:c.603-6229T>C

Variant names:

• chr15-74016599-T-C
• rs4886844
• NM_033238.3:c.603-6229T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033238.3. 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
	PML	NM_033238.3	MANE Select	c.603-6229T>C		intron	N/A	NP_150241.2
	PML	NM_033239.3		c.603-6229T>C		intron	N/A	NP_150242.1
	PML	NM_033250.3		c.603-6229T>C		intron	N/A	NP_150253.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PML	ENST00000268058.8	TSL:1 MANE Select	c.603-6229T>C		intron	N/A	ENSP00000268058.3
	PML	ENST00000565898.5	TSL:1	c.603-6229T>C		intron	N/A	ENSP00000455838.1
	PML	ENST00000268059.10	TSL:1	c.603-6229T>C		intron	N/A	ENSP00000268059.6

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

African (AFR) AF: 0.375 AC: 15532 AN: 41418

American (AMR) AF: 0.517 AC: 7892 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1561 AN: 3464

East Asian (EAS) AF: 0.445 AC: 2295 AN: 5154

South Asian (SAS) AF: 0.483 AC: 2330 AN: 4820

European-Finnish (FIN) AF: 0.598 AC: 6219 AN: 10402

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38216 AN: 67926

Other (OTH) AF: 0.487 AC: 1027 AN: 2108

Alfa AF: 0.538 Hom.: 11034

Bravo AF: 0.485

Asia WGS AF: 0.451 AC: 1568 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		0.67
Mutation Taster		=100/0	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: rs4886844; hg19: chr15-74308940;