15-74044292-T-C

Position:

• chr15-74044292-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.1933T>C​(p.Phe645Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,613,806 control chromosomes in the GnomAD database, including 145,396 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.32 (9793 hom., cov: 32)
  • Exomes 𝑓: 0.42 (135603 hom.)
• Consequence: PML NM_033238.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0220

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 (MetaRNN=1.245439E-4).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PML	NM_033238.3	c.1933T>C	p.Phe645Leu	missense_variant	9/9	ENST00000268058.8	NP_150241.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PML	ENST00000268058.8	c.1933T>C	p.Phe645Leu	missense_variant	9/9	1	NM_033238.3	ENSP00000268058.3
PML	ENST00000565898.5	c.1789T>C	p.Phe597Leu	missense_variant	8/8	1		ENSP00000455838.1

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48167 AN: 151974 Hom.: 9795 Cov.: 32

Gnomad AFR AF: 0.0980

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.00540

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.330

GnomAD3 exomes AF: 0.350 AC: 87870 AN: 251222 Hom.: 18130 AF XY: 0.359 AC XY: 48748 AN XY: 135812

Gnomad AFR exome AF: 0.0888

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.00343

Gnomad SAS exome AF: 0.278

Gnomad FIN exome AF: 0.400

Gnomad NFE exome AF: 0.460

Gnomad OTH exome AF: 0.384

GnomAD4 exome AF: 0.417 AC: 610261 AN: 1461714 Hom.: 135603 Cov.: 47 AF XY: 0.415 AC XY: 301850 AN XY: 727186

Gnomad4 AFR exome AF: 0.0834

Gnomad4 AMR exome AF: 0.311

Gnomad4 ASJ exome AF: 0.402

Gnomad4 EAS exome AF: 0.00401

Gnomad4 SAS exome AF: 0.281

Gnomad4 FIN exome AF: 0.405

Gnomad4 NFE exome AF: 0.460

Gnomad4 OTH exome AF: 0.385

GnomAD4 genome AF: 0.317 AC: 48160 AN: 152092 Hom.: 9793 Cov.: 32 AF XY: 0.313 AC XY: 23307 AN XY: 74348

Gnomad4 AFR AF: 0.0978

Gnomad4 AMR AF: 0.324

Gnomad4 ASJ AF: 0.413

Gnomad4 EAS AF: 0.00522

Gnomad4 SAS AF: 0.276

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.325

Alfa AF: 0.424 Hom.: 35276

Bravo AF: 0.304

TwinsUK AF: 0.470 AC: 1744

ALSPAC AF: 0.461 AC: 1775

ESP6500AA AF: 0.106 AC: 467

ESP6500EA AF: 0.462 AC: 3970

ExAC AF: 0.350 AC: 42507

Asia WGS AF: 0.0990 AC: 346 AN: 3478

EpiCase AF: 0.463

EpiControl AF: 0.470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.25
DANN	Benign	0.72
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.00012	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.31	N;N
REVEL	Benign	0.029
Sift	Benign	0.22	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0	B;B
Vest4		0.035
MutPred		0.17		Gain of helix (P = 0.062);.;
MPC		0.24
ClinPred		0.0016	T
GERP RS		-3.3
Varity_R		0.034
gMVP		0.26

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: rs5742915; hg19: chr15-74336633; COSMIC: COSV51444435; COSMIC: COSV51444435;