rs9479

Variant names:

• chr15-74036235-A-G
• rs9479
• ENST00000268059.10:c.*284A>G

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.*284A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,526,804 control chromosomes in the GnomAD database, including 192,950 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (19502 hom., cov: 31)
  • Exomes 𝑓: 0.50 (173448 hom.)
• Consequence: PML ENST00000268059.10 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.515
• Publications: 17 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 (BayesDel_noAF=-0.89).
• BP6: Variant 15-74036235-A-G is Benign according to our data. Variant chr15-74036235-A-G is described in ClinVar as Benign. ClinVar VariationId is 1288742.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PML	NM_033238.3	c.1710+1705A>G		intron_variant	Intron 7 of 8	ENST00000268058.8	NP_150241.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PML	ENST00000268058.8	c.1710+1705A>G		intron_variant	Intron 7 of 8	1	NM_033238.3	ENSP00000268058.3

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76655 AN: 151700 Hom.: 19493 Cov.: 31

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.515

GnomAD4 exome AF: 0.501 AC: 688672 AN: 1374986 Hom.: 173448 Cov.: 51 AF XY: 0.502 AC XY: 340204 AN XY: 677800

African (AFR) AF: 0.473 AC: 14969 AN: 31654

American (AMR) AF: 0.512 AC: 18098 AN: 35334

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 11810 AN: 23632

East Asian (EAS) AF: 0.652 AC: 23625 AN: 36246

South Asian (SAS) AF: 0.525 AC: 40134 AN: 76450

European-Finnish (FIN) AF: 0.563 AC: 19436 AN: 34540

Middle Eastern (MID) AF: 0.489 AC: 1943 AN: 3976

European-Non Finnish (NFE) AF: 0.493 AC: 529838 AN: 1075788

Other (OTH) AF: 0.502 AC: 28819 AN: 57366

GnomAD4 genome AF: 0.505 AC: 76715 AN: 151818 Hom.: 19502 Cov.: 31 AF XY: 0.509 AC XY: 37749 AN XY: 74188

African (AFR) AF: 0.473 AC: 19578 AN: 41354

American (AMR) AF: 0.532 AC: 8119 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1670 AN: 3468

East Asian (EAS) AF: 0.636 AC: 3270 AN: 5144

South Asian (SAS) AF: 0.527 AC: 2535 AN: 4814

European-Finnish (FIN) AF: 0.561 AC: 5918 AN: 10542

Middle Eastern (MID) AF: 0.425 AC: 124 AN: 292

European-Non Finnish (NFE) AF: 0.502 AC: 34105 AN: 67906

Other (OTH) AF: 0.517 AC: 1092 AN: 2112

Alfa AF: 0.497 Hom.: 12461

Bravo AF: 0.497

Asia WGS AF: 0.596 AC: 2070 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24886876) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.73
PhyloP100		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs9479; hg19: chr15-74328576; COSMIC: COSV51446452; COSMIC: COSV51446452;