chr15-74011008-C-A

Variant names:

• chr15-74011008-C-A
• rs11072463
• NM_033238.3:c.603-11820C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033238.3(PML):​c.603-11820C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 152,034 control chromosomes in the GnomAD database, including 29,032 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 0.62 (29032 hom., cov: 32)
• Consequence: PML NM_033238.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.443
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.64 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PML	NM_033238.3	c.603-11820C>A		intron_variant	Intron 2 of 8	ENST00000268058.8	NP_150241.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PML	ENST00000268058.8	c.603-11820C>A		intron_variant	Intron 2 of 8	1	NM_033238.3	ENSP00000268058.3

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93703 AN: 151916 Hom.: 29020 Cov.: 32

Gnomad AFR AF: 0.558

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.634

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.606

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

GnomAD4 genome AF: 0.617 AC: 93767 AN: 152034 Hom.: 29032 Cov.: 32 AF XY: 0.619 AC XY: 45995 AN XY: 74304

African (AFR) AF: 0.558 AC: 23120 AN: 41442

American (AMR) AF: 0.592 AC: 9052 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2132 AN: 3472

East Asian (EAS) AF: 0.635 AC: 3283 AN: 5172

South Asian (SAS) AF: 0.601 AC: 2897 AN: 4820

European-Finnish (FIN) AF: 0.716 AC: 7563 AN: 10556

Middle Eastern (MID) AF: 0.510 AC: 149 AN: 292

European-Non Finnish (NFE) AF: 0.645 AC: 43864 AN: 67970

Other (OTH) AF: 0.608 AC: 1285 AN: 2114

Alfa AF: 0.630 Hom.: 129150

Bravo AF: 0.603

Asia WGS AF: 0.619 AC: 2150 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.53
DANN	Benign	0.63
PhyloP100		-0.44
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: rs11072463; hg19: chr15-74303349;