Genetic Variant NM_033238.3:c.82A>C (chr15-73994894-A-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_033238.3(PML):c.82A>C(p.Thr28Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,546,602 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0080 ( 18 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 20 hom. )

Consequence

PML
NM_033238.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.12

Publications

2 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024793148).

BP6

Variant 15-73994894-A-C is Benign according to our data. Variant chr15-73994894-A-C is described in ClinVar as Benign. ClinVar VariationId is 776928.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00804 (1211/150560) while in subpopulation AFR AF = 0.028 (1145/40828). AF 95% confidence interval is 0.0267. There are 18 homozygotes in GnomAd4. There are 586 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1211 AD gene.

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>C	p.Thr28Pro	missense	Exon 1 of 9	NP_150241.2	P29590-1
PML	NM_033239.3		c.82A>C	p.Thr28Pro	missense	Exon 1 of 8	NP_150242.1	P29590-8
PML	NM_033250.3		c.82A>C	p.Thr28Pro	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>C	p.Thr28Pro	missense	Exon 1 of 9	ENSP00000268058.3	P29590-1
PML	ENST00000565898.5	TSL:1	c.82A>C	p.Thr28Pro	missense	Exon 1 of 8	ENSP00000455838.1	P29590-11
PML	ENST00000268059.10	TSL:1	c.82A>C	p.Thr28Pro	missense	Exon 1 of 8	ENSP00000268059.6	P29590-8

Frequencies

GnomAD3 genomes

AF:

0.00804

AC:

1209

AN:

150460

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0281

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00285

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000163

Gnomad OTH

AF:

0.00485

GnomAD2 exomes

AF:

0.00161

AC:

245

AN:

152548

AF XY:

0.00148

show subpopulations

Gnomad AFR exome

AF:

0.0300

Gnomad AMR exome

AF:

0.000876

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000864

Gnomad OTH exome

AF:

0.000231

GnomAD4 exome

AF:

0.000824

AC:

1150

AN:

1396042

Hom.:

Cov.:

AF XY:

0.000774

AC XY:

533

AN XY:

689064

show subpopulations

African (AFR)

AF:

0.0286

AC:

905

AN:

31684

American (AMR)

AF:

0.00148

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:

0.0000378

AC:

AN:

79282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48242

Middle Eastern (MID)

AF:

0.000533

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.0000818

AC:

AN:

1075768

Other (OTH)

AF:

0.00167

AC:

AN:

57924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

101

151

202

252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00804

AC:

1211

AN:

150560

Hom.:

Cov.:

AF XY:

0.00797

AC XY:

586

AN XY:

73536

show subpopulations

African (AFR)

AF:

0.0280

AC:

1145

AN:

40828

American (AMR)

AF:

0.00284

AC:

AN:

15122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5110

South Asian (SAS)

AF:

0.000213

AC:

AN:

4702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10416

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000163

AC:

AN:

67650

Other (OTH)

AF:

0.00480

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

112

167

223

279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00264

Hom.:

Bravo

AF:

0.00915

ESP6500AA

AF:

0.00248

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000645

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.056

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.28

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.49

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.20

PhyloP100

-2.1

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.60

REVEL

Benign

0.037

Sift

Benign

0.25

Sift4G

Benign

0.19

Polyphen

0.0010

Vest4

0.088

MVP

0.26

MPC

1.1

ClinPred

0.0038

GERP RS

-4.5

PromoterAI

-0.0077

Neutral

(source)

Varity_R

0.12

gMVP

0.13

Mutation Taster

=99/1

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over