chr15-74023223-T-G

Position:

• chr15-74023223-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_033238.3(PML):​c.998T>G​(p.Val333Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PML NM_033238.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

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]

PML (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PML	NM_033238.3	c.998T>G	p.Val333Gly	missense_variant	3/9	ENST00000268058.8	NP_150241.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PML	ENST00000268058.8	c.998T>G	p.Val333Gly	missense_variant	3/9	1	NM_033238.3	ENSP00000268058.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2024

The c.998T>G (p.V333G) alteration is located in exon 3 (coding exon 3) of the PML gene. This alteration results from a T to G substitution at nucleotide position 998, causing the valine (V) at amino acid position 333 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;.;.;.;D;.;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;.;.;T;T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M;M;M;M;M;M;M;.
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0060	D;D;D;D;D;D;T;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;.;D;D;D;D;.;D;D;D;D;D;D;.
Vest4		0.56
MutPred		0.51		Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);Loss of stability (P = 0.0027);
MVP		0.85
MPC		2.2
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.46
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-74315564;