dbSNP rs779135665: PML:p.Pro41Ala (chr15-73994933-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_033238.3(PML):c.121C>G(p.Pro41Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,544,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

PML
NM_033238.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.87

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08089867).

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PML	NM_033238.3 link	c.121C>G	p.Pro41Ala	missense_variant	Exon 1 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.121C>G	p.Pro41Ala	missense_variant	Exon 1 of 9	1	NM_033238.3	ENSP00000268058.3		P29590-1

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000112

AC:

AN:

142778

Hom.:

AF XY:

0.000117

AC XY:

AN XY:

76918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000423

Gnomad ASJ exome

AF:

0.000774

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000449

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000952

Gnomad OTH exome

AF:

0.000736

GnomAD4 exome

AF:

0.000103

AC:

143

AN:

1392434

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

686426

show subpopulations

Gnomad4 AFR exome

AF:

0.0000319

Gnomad4 AMR exome

AF:

0.000288

Gnomad4 ASJ exome

AF:

0.000729

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000177

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000669

Gnomad4 OTH exome

AF:

0.000416

GnomAD4 genome

AF:

0.0000790

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000253

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000359

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

.;.;.;.;T;.;.;.;.;.;.;.;.;T

Eigen

Benign

0.084

Eigen_PC

Benign

-0.030

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D;.;.;D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.081

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.3

M;M;M;M;M;M;M;M;M;M;M;M;M;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.3

N;N;D;D;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.051

Sift

Uncertain

0.020

D;T;D;D;D;D;D;D;T;D;D;D;T;D

Sift4G

Benign

0.24

T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.97

D;.;D;D;D;D;.;D;D;D;D;D;D;.

Vest4

0.14

MutPred

0.21

Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);Loss of glycosylation at P41 (P = 0.0076);

MVP

0.74

MPC

1.4

ClinPred

0.30

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.16

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