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GeneBe

15-74023017-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_033238.3(PML):c.792C>T(p.Ala264=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00703 in 1,607,302 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0049 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0072 ( 54 hom. )

Consequence

PML
NM_033238.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.82
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 15-74023017-C-T is Benign according to our data. Variant chr15-74023017-C-T is described in ClinVar as [Benign]. Clinvar id is 774496.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-2.82 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 751 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PMLNM_033238.3 linkuse as main transcriptc.792C>T p.Ala264= synonymous_variant 3/9 ENST00000268058.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PMLENST00000268058.8 linkuse as main transcriptc.792C>T p.Ala264= synonymous_variant 3/91 NM_033238.3 P1P29590-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00493
AC:
751
AN:
152216
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00154
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00746
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00763
Gnomad OTH
AF:
0.00430
GnomAD3 exomes
AF:
0.00428
AC:
983
AN:
229808
Hom.:
2
AF XY:
0.00413
AC XY:
523
AN XY:
126706
show subpopulations
Gnomad AFR exome
AF:
0.00154
Gnomad AMR exome
AF:
0.00260
Gnomad ASJ exome
AF:
0.00374
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000992
Gnomad FIN exome
AF:
0.00245
Gnomad NFE exome
AF:
0.00759
Gnomad OTH exome
AF:
0.00382
GnomAD4 exome
AF:
0.00725
AC:
10542
AN:
1454968
Hom.:
54
Cov.:
33
AF XY:
0.00702
AC XY:
5085
AN XY:
723868
show subpopulations
Gnomad4 AFR exome
AF:
0.00123
Gnomad4 AMR exome
AF:
0.00252
Gnomad4 ASJ exome
AF:
0.00323
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000930
Gnomad4 FIN exome
AF:
0.00308
Gnomad4 NFE exome
AF:
0.00880
Gnomad4 OTH exome
AF:
0.00613
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00493
AC:
751
AN:
152334
Hom.:
1
Cov.:
33
AF XY:
0.00476
AC XY:
355
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.00154
Gnomad4 AMR
AF:
0.00745
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00377
Gnomad4 NFE
AF:
0.00763
Gnomad4 OTH
AF:
0.00425
Alfa
AF:
0.00629
Hom.:
0
Bravo
AF:
0.00497

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJul 07, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.75
Cadd
Benign
5.8
Dann
Benign
0.76
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2

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.

Other links and lift over

dbSNP: rs17849259; hg19: chr15-74315358; COSMIC: COSV99166947; COSMIC: COSV99166947; API