rs12917449

chr15-74039318-A-Cchr15-74039318-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033238.3(PML):c.1711-3671A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 152,212 control chromosomes in the GnomAD database, including 2,339 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2339 hom., cov: 33)
• Consequence: PML NM_033238.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.229

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PML	NM_033238.3	c.1711-3671A>C		intron_variant		ENST00000268058.8
PML	NM_002675.4	c.1711-3671A>C		intron_variant
PML	NM_033246.3	c.*36-3671A>C		intron_variant
PML	NM_033249.3	c.1567-3671A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PML	ENST00000268058.8	c.1711-3671A>C		intron_variant		1	NM_033238.3	P1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25319 AN: 152094 Hom.: 2341 Cov.: 33

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0775

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.132

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.166 AC: 25321 AN: 152212 Hom.: 2339 Cov.: 33 AF XY: 0.166 AC XY: 12319 AN XY: 74394

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0775

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.196

Gnomad4 OTH AF: 0.128

Alfa AF: 0.169 Hom.: 2353

Bravo AF: 0.151

Asia WGS AF: 0.144 AC: 500 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	4.7
Dann	Benign	0.54

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: rs12917449; hg19: chr15-74331659;