dbSNP rs5742915: PML:p.Phe645Leu (chr15-74044292-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.32 ( 9793 hom., cov: 32)

Exomes 𝑓: 0.42 ( 135603 hom. )

Consequence

PML
NM_033238.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0220

Publications

112 publications found

Variant links:

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]

PML links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PML	NM_033238.3 link	c.1933T>C	p.Phe645Leu	missense_variant	Exon 9 of 9	ENST00000268058.8	NP_150241.2	P29590-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PML	ENST00000268058.8 link	c.1933T>C	p.Phe645Leu	missense_variant	Exon 9 of 9	1	NM_033238.3	ENSP00000268058.3		P29590-1
PML	ENST00000565898.5 link	c.1789T>C	p.Phe597Leu	missense_variant	Exon 8 of 8	1		ENSP00000455838.1		P29590-11

Frequencies

GnomAD3 genomes

AF:

0.317

AC:

48167

AN:

151974

Hom.:

9795

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.350

AC:

87870

AN:

251222

AF XY:

0.359

show subpopulations

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 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.:

AF XY:

0.415

AC XY:

301850

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.0834

AC:

2793

AN:

33478

American (AMR)

AF:

0.311

AC:

13920

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.402

AC:

10495

AN:

26136

East Asian (EAS)

AF:

0.00401

AC:

159

AN:

39700

South Asian (SAS)

AF:

0.281

AC:

24257

AN:

86258

European-Finnish (FIN)

AF:

0.405

AC:

21621

AN:

53332

Middle Eastern (MID)

AF:

0.402

AC:

2316

AN:

5768

European-Non Finnish (NFE)

AF:

0.460

AC:

511430

AN:

1111926

Other (OTH)

AF:

0.385

AC:

23270

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

21113

42225

63338

84450

105563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14794

29588

44382

59176

73970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.317

AC:

48160

AN:

152092

Hom.:

9793

Cov.:

AF XY:

0.313

AC XY:

23307

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0978

AC:

4058

AN:

41508

American (AMR)

AF:

0.324

AC:

4960

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.413

AC:

1432

AN:

3466

East Asian (EAS)

AF:

0.00522

AC:

AN:

5170

South Asian (SAS)

AF:

0.276

AC:

1330

AN:

4824

European-Finnish (FIN)

AF:

0.404

AC:

4274

AN:

10572

Middle Eastern (MID)

AF:

0.456

AC:

134

AN:

294

European-Non Finnish (NFE)

AF:

0.453

AC:

30763

AN:

67944

Other (OTH)

AF:

0.325

AC:

686

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1473

2945

4418

5890

7363

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.408

Hom.:

65944

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

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.25

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.41

T;T

MetaRNN

Benign

0.00012

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

L;.

PhyloP100

0.022

PrimateAI

Benign

0.36

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

GERP RS

-3.3

Varity_R

0.034

gMVP

0.26

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over