Variant chr15-73994832-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_033238.3(PML):c.20G>T(p.Arg7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,557,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

PML
NM_033238.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.770

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=0.18177465).

BS2

High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PML	NM_033238.3 linkuse as main transcript	c.20G>T	p.Arg7Leu	missense_variant	1/9	ENST00000268058.8	NP_150241.2	P29590-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PML	ENST00000268058.8 linkuse as main transcript	c.20G>T	p.Arg7Leu	missense_variant	1/9	1	NM_033238.3	ENSP00000268058.3		P29590-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

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

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1405534

Hom.:

Cov.:

AF XY:

0.0000115

AC XY:

AN XY:

693740

show subpopulations

Gnomad4 AFR exome

AF:

0.0000312

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000222

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

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:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.20G>T (p.R7L) alteration is located in exon 1 (coding exon 1) of the PML gene. This alteration results from a G to T substitution at nucleotide position 20, causing the arginine (R) at amino acid position 7 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

.;.;.;.;D;.;.;.;.;.;.;.;.;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.025

MetaRNN

Benign

0.18

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

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

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.4

N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.079

Sift

Benign

0.12

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

Sift4G

Benign

0.22

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

Polyphen

0.94

P;.;D;P;P;P;.;D;P;D;D;P;P;.

Vest4

0.22

MutPred

0.23

Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);Loss of methylation at R7 (P = 0.0955);

MVP

0.69

MPC

1.3

ClinPred

0.60

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.15

gMVP

0.20

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over