15-74023127-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033238.3(PML):c.902T>C(p.Val301Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PML NM_033238.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3760498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PML	NM_033238.3	c.902T>C	p.Val301Ala	missense_variant	3/9	ENST00000268058.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PML	ENST00000268058.8	c.902T>C	p.Val301Ala	missense_variant	3/9	1	NM_033238.3	P1

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

Apr 05, 2023

The c.902T>C (p.V301A) alteration is located in exon 3 (coding exon 3) of the PML gene. This alteration results from a T to C substitution at nucleotide position 902, causing the valine (V) at amino acid position 301 to be replaced by an alanine (A). 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	21
Dann	Benign	0.96
Eigen	Benign	0.023
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;.;.;D;D;D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.9	L;L;L;L;L;L;L;L;L;L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.66	P;.;P;D;D;P;.;D;D;D;D;P;D;.
Vest4		0.51
MutPred		0.36		Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);Loss of stability (P = 0.0859);
MVP		0.62
MPC		1.8
ClinPred		0.75	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.11
gMVP		0.90

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: chr15-74315468;