Genetic Variant PML:p.Thr28Ser (chr15-73994894-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033238.3(PML):c.82A>T(p.Thr28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,396,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T28P) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PML
NM_033238.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.12

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.028712869).

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.82A>T	p.Thr28Ser	missense	Exon 1 of 9	NP_150241.2	P29590-1
PML	NM_033239.3		c.82A>T	p.Thr28Ser	missense	Exon 1 of 8	NP_150242.1	P29590-8
PML	NM_033250.3		c.82A>T	p.Thr28Ser	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.82A>T	p.Thr28Ser	missense	Exon 1 of 9	ENSP00000268058.3	P29590-1
PML	ENST00000565898.5	TSL:1	c.82A>T	p.Thr28Ser	missense	Exon 1 of 8	ENSP00000455838.1	P29590-11
PML	ENST00000268059.10	TSL:1	c.82A>T	p.Thr28Ser	missense	Exon 1 of 8	ENSP00000268059.6	P29590-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1396054

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689068

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31694

American (AMR)

AF:

0.00

AC:

AN:

36364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25106

East Asian (EAS)

AF:

0.00

AC:

AN:

36044

South Asian (SAS)

AF:

0.00

AC:

AN:

79282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1075770

Other (OTH)

AF:

0.00

AC:

AN:

57924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.0060

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.28

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.48

M_CAP

Benign

0.0035

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.2

PhyloP100

-2.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.46

REVEL

Benign

0.036

Sift

Benign

0.65

Sift4G

Benign

0.77

Polyphen

0.0020

Vest4

0.085

MutPred

0.31

Gain of glycosylation at P29 (P = 0.0878)

MVP

0.24

MPC

0.76

ClinPred

0.059

GERP RS

-4.5

PromoterAI

-0.070

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.033

gMVP

0.072

Mutation Taster

=97/3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over