dbSNP rs779135665: PML:p.Pro41Ser (chr15-73994933-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033238.3(PML):c.121C>T(p.Pro41Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,392,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

PML
NM_033238.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22303519).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PML	NM_033238.3	MANE Select	c.121C>T	p.Pro41Ser	missense	Exon 1 of 9	NP_150241.2	P29590-1
PML	NM_033239.3		c.121C>T	p.Pro41Ser	missense	Exon 1 of 8	NP_150242.1	P29590-8
PML	NM_033250.3		c.121C>T	p.Pro41Ser	missense	Exon 1 of 7	NP_150253.2	P29590-13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PML	ENST00000268058.8	TSL:1 MANE Select	c.121C>T	p.Pro41Ser	missense	Exon 1 of 9	ENSP00000268058.3	P29590-1
PML	ENST00000565898.5	TSL:1	c.121C>T	p.Pro41Ser	missense	Exon 1 of 8	ENSP00000455838.1	P29590-11
PML	ENST00000268059.10	TSL:1	c.121C>T	p.Pro41Ser	missense	Exon 1 of 8	ENSP00000268059.6	P29590-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000287

AC:

AN:

1392434

Hom.:

Cov.:

AF XY:

0.00000583

AC XY:

AN XY:

686426

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31318

American (AMR)

AF:

0.00

AC:

AN:

34668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24680

East Asian (EAS)

AF:

0.00

AC:

AN:

35712

South Asian (SAS)

AF:

0.00

AC:

AN:

78884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48026

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00000372

AC:

AN:

1075816

Other (OTH)

AF:

0.00

AC:

AN:

57690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Benign

0.084

Eigen_PC

Benign

-0.026

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.012

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

PhyloP100

1.9

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.2

REVEL

Benign

0.046

Sift

Uncertain

0.026

Sift4G

Uncertain

0.044

Polyphen

0.95

Vest4

0.20

MutPred

0.27

Gain of phosphorylation at P41 (P = 6e-04)

MVP

0.76

MPC

1.3

ClinPred

0.92

GERP RS

2.9

PromoterAI

-0.030

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.19

Mutation Taster

=96/4

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over