Variant rs5742915 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0220

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 made for transcript

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	UniProt
PML	NM_033238.3 linkuse as main transcript	c.1933T>C	p.Phe645Leu	missense_variant	9/9	ENST00000268058.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PML	ENST00000268058.8 linkuse as main transcript	c.1933T>C	p.Phe645Leu	missense_variant	9/9	1	NM_033238.3	P1	P29590-1
PML	ENST00000565898.5 linkuse as main transcript	c.1789T>C	p.Phe597Leu	missense_variant	8/8	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

GnomAD3 exomes

AF:

0.350

AC:

87870

AN:

251222

Hom.:

18130

AF XY:

0.359

AC XY:

48748

AN XY:

135812

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 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.:

AF XY:

0.415

AC XY:

301850

AN XY:

727186

show subpopulations

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.:

AF XY:

0.313

AC XY:

23307

AN XY:

74348

show subpopulations

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

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

LIST_S2

Benign

0.41

T;T

MetaRNN

Benign

0.00012

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

1.0

P;P

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over