chr15-74035800-G-T

Position:

• chr15-74035800-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000268059.10(PML):​c.2339G>T​(p.Gly780Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,613,738 control chromosomes in the GnomAD database, including 107,662 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (9892 hom., cov: 32)
  • Exomes 𝑓: 0.36 (97770 hom.)
• Consequence: PML ENST00000268059.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.320

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.7407875E-4).
• BP6: Variant 15-74035800-G-T is Benign according to our data. Variant chr15-74035800-G-T is described in ClinVar as [Benign]. Clinvar id is 403330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PML	NM_033238.3	c.1710+1270G>T		intron_variant		ENST00000268058.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PML	ENST00000268058.8	c.1710+1270G>T		intron_variant		1	NM_033238.3	P1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54347 AN: 151898 Hom.: 9887 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.355

GnomAD3 exomes AF: 0.363 AC: 91105 AN: 250864 Hom.: 17084 AF XY: 0.356 AC XY: 48335 AN XY: 135758

Gnomad AFR exome AF: 0.317

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.402

Gnomad SAS exome AF: 0.280

Gnomad FIN exome AF: 0.415

Gnomad NFE exome AF: 0.362

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.363 AC: 531103 AN: 1461724 Hom.: 97770 Cov.: 56 AF XY: 0.360 AC XY: 262010 AN XY: 727160

Gnomad4 AFR exome AF: 0.318

Gnomad4 AMR exome AF: 0.440

Gnomad4 ASJ exome AF: 0.238

Gnomad4 EAS exome AF: 0.430

Gnomad4 SAS exome AF: 0.281

Gnomad4 FIN exome AF: 0.414

Gnomad4 NFE exome AF: 0.368

Gnomad4 OTH exome AF: 0.345

GnomAD4 genome AF: 0.358 AC: 54382 AN: 152014 Hom.: 9892 Cov.: 32 AF XY: 0.358 AC XY: 26597 AN XY: 74276

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.414

Gnomad4 SAS AF: 0.277

Gnomad4 FIN AF: 0.408

Gnomad4 NFE AF: 0.371

Gnomad4 OTH AF: 0.356

Alfa AF: 0.359 Hom.: 16912

Bravo AF: 0.355

TwinsUK AF: 0.361 AC: 1340

ALSPAC AF: 0.369 AC: 1422

ESP6500AA AF: 0.321 AC: 1412

ESP6500EA AF: 0.359 AC: 3088

ExAC AF: 0.359 AC: 43607

Asia WGS AF: 0.355 AC: 1235 AN: 3478

EpiCase AF: 0.347

EpiControl AF: 0.342

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

PML-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.2
DANN	Benign	0.23
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	0.00037	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.013
Sift	Benign	0.22	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.077	B;B
Vest4		0.080
ClinPred		0.0020	T
GERP RS		-2.4

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

Other links and lift over

dbSNP: rs743581; hg19: chr15-74328141; COSMIC: COSV51443888; COSMIC: COSV51443888;