ENST00000268059.10:c.2339G>T

Variant names:

• chr15-74035800-G-T
• rs743581
• ENST00000268059.10:c.2339G>T

Variant summary

Our verdict is Benign. The variant received -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. 13/16 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
• Publications: 36 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000268059.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PML	NM_033238.3	MANE Select	c.1710+1270G>T		intron	N/A	NP_150241.2
	PML	NM_033239.3		c.2339G>T	p.Gly780Val	missense	Exon 8 of 8	NP_150242.1
	PML	NM_033250.3		c.2195G>T	p.Gly732Val	missense	Exon 7 of 7	NP_150253.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PML	ENST00000268059.10	TSL:1	c.2339G>T	p.Gly780Val	missense	Exon 8 of 8	ENSP00000268059.6
	PML	ENST00000354026.10	TSL:1	c.2195G>T	p.Gly732Val	missense	Exon 7 of 7	ENSP00000315434.8
	PML	ENST00000435786.6	TSL:1	c.*1144G>T		3_prime_UTR	Exon 7 of 7	ENSP00000395576.2

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

GnomAD2 exomes AF: 0.363 AC: 91105 AN: 250864 AF XY: 0.356

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 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

African (AFR) AF: 0.318 AC: 10648 AN: 33478

American (AMR) AF: 0.440 AC: 19666 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 6230 AN: 26136

East Asian (EAS) AF: 0.430 AC: 17085 AN: 39700

South Asian (SAS) AF: 0.281 AC: 24270 AN: 86256

European-Finnish (FIN) AF: 0.414 AC: 22099 AN: 53328

Middle Eastern (MID) AF: 0.258 AC: 1487 AN: 5766

European-Non Finnish (NFE) AF: 0.368 AC: 408807 AN: 1111942

Other (OTH) AF: 0.345 AC: 20811 AN: 60394

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

African (AFR) AF: 0.318 AC: 13166 AN: 41460

American (AMR) AF: 0.423 AC: 6464 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 786 AN: 3470

East Asian (EAS) AF: 0.414 AC: 2125 AN: 5132

South Asian (SAS) AF: 0.277 AC: 1333 AN: 4810

European-Finnish (FIN) AF: 0.408 AC: 4315 AN: 10580

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25236 AN: 67956

Other (OTH) AF: 0.356 AC: 753 AN: 2114

Alfa AF: 0.360 Hom.: 21813

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

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

PML-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
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
MetaRNN	Benign	0.00037	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.32
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.013
Sift	Benign	0.22	T
Sift4G	Benign	0.28	T
Polyphen		0.077	B
Vest4		0.080
ClinPred		0.0020	T
GERP RS		-2.4
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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