rs743580

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033239.3(PML):c.2314A>G(p.Ser772Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,613,706 control chromosomes in the GnomAD database, including 206,528 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 20370 hom., cov: 32)

Exomes 𝑓: 0.50 ( 186158 hom. )

Consequence

PML
NM_033239.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.145

Publications

41 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2334185E-5).

BP6

Variant 15-74035775-A-G is Benign according to our data. Variant chr15-74035775-A-G is described in ClinVar as Benign. ClinVar VariationId is 403329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033239.3. 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.1710+1245A>G		intron	N/A	NP_150241.2	P29590-1
PML	NM_033239.3		c.2314A>G	p.Ser772Gly	missense	Exon 8 of 8	NP_150242.1	P29590-8
PML	NM_033250.3		c.2170A>G	p.Ser724Gly	missense	Exon 7 of 7	NP_150253.2	P29590-13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PML	ENST00000268059.10	TSL:1	c.2314A>G	p.Ser772Gly	missense	Exon 8 of 8	ENSP00000268059.6	P29590-8
PML	ENST00000354026.10	TSL:1	c.2170A>G	p.Ser724Gly	missense	Exon 7 of 7	ENSP00000315434.8	P29590-13
PML	ENST00000435786.6	TSL:1	c.*1119A>G		3_prime_UTR	Exon 7 of 7	ENSP00000395576.2	P29590-2

Frequencies

GnomAD3 genomes

AF:

0.517

AC:

78463

AN:

151830

Hom.:

20360

Cov.:

show subpopulations

Gnomad AFR

AF:

0.514

Gnomad AMI

AF:

0.333

Gnomad AMR

AF:

0.535

Gnomad ASJ

AF:

0.481

Gnomad EAS

AF:

0.636

Gnomad SAS

AF:

0.531

Gnomad FIN

AF:

0.560

Gnomad MID

AF:

0.421

Gnomad NFE

AF:

0.502

Gnomad OTH

AF:

0.521

GnomAD2 exomes

AF:

0.523

AC:

131270

AN:

250958

AF XY:

0.521

show subpopulations

Gnomad AFR exome

AF:

0.520

Gnomad AMR exome

AF:

0.531

Gnomad ASJ exome

AF:

0.501

Gnomad EAS exome

AF:

0.631

Gnomad FIN exome

AF:

0.564

Gnomad NFE exome

AF:

0.496

Gnomad OTH exome

AF:

0.521

GnomAD4 exome

AF:

0.503

AC:

735417

AN:

1461758

Hom.:

186158

Cov.:

AF XY:

0.504

AC XY:

366435

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.517

AC:

17314

AN:

33474

American (AMR)

AF:

0.526

AC:

23535

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.498

AC:

13018

AN:

26136

East Asian (EAS)

AF:

0.651

AC:

25828

AN:

39700

South Asian (SAS)

AF:

0.530

AC:

45691

AN:

86254

European-Finnish (FIN)

AF:

0.561

AC:

29940

AN:

53352

Middle Eastern (MID)

AF:

0.483

AC:

2785

AN:

5768

European-Non Finnish (NFE)

AF:

0.492

AC:

546800

AN:

1111960

Other (OTH)

AF:

0.505

AC:

30506

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

24189

48378

72568

96757

120946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16114

32228

48342

64456

80570

<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:

0.517

AC:

78527

AN:

151948

Hom.:

20370

Cov.:

AF XY:

0.520

AC XY:

38647

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.514

AC:

21308

AN:

41420

American (AMR)

AF:

0.535

AC:

8186

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.481

AC:

1670

AN:

3472

East Asian (EAS)

AF:

0.636

AC:

3262

AN:

5128

South Asian (SAS)

AF:

0.530

AC:

2548

AN:

4810

European-Finnish (FIN)

AF:

0.560

AC:

5934

AN:

10588

Middle Eastern (MID)

AF:

0.429

AC:

126

AN:

294

European-Non Finnish (NFE)

AF:

0.502

AC:

34088

AN:

67928

Other (OTH)

AF:

0.523

AC:

1103

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1986

3973

5959

7946

9932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

700

1400

2100

2800

3500

<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:

0.504

Hom.:

45554

Bravo

AF:

0.511

TwinsUK

AF:

0.482

AC:

1789

ALSPAC

AF:

0.488

AC:

1881

ESP6500AA

AF:

0.512

AC:

2250

ESP6500EA

AF:

0.493

AC:

4233

ExAC

AF:

0.522

AC:

63345

Asia WGS

AF:

0.601

AC:

2087

AN:

3478

EpiCase

AF:

0.495

EpiControl

AF:

0.488

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

PML-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.6

(source)

DANN

Benign

0.12

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.00021

LIST_S2

Benign

0.21

MetaRNN

Benign

0.000012

MetaSVM

Benign

-0.93

PhyloP100

0.14

PROVEAN

Benign

0.63

REVEL

Benign

0.049

Sift

Benign

1.0

Sift4G

Benign

0.54

Polyphen

0.0

Vest4

0.013

ClinPred

0.0013

GERP RS

0.62

Mutation Taster

=100/0

polymorphism (auto)

(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