15-74023162-G-A

Variant names:

• chr15-74023162-G-A
• NM_033238.3:c.937G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033238.3(PML):​c.937G>A​(p.Ala313Thr) 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. 13/21 in silico tools predict a benign outcome for this variant. 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: 0.400

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12763757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PML	NM_033238.3	c.937G>A	p.Ala313Thr	missense_variant	Exon 3 of 9	ENST00000268058.8	NP_150241.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PML	ENST00000268058.8	c.937G>A	p.Ala313Thr	missense_variant	Exon 3 of 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

Jan 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.937G>A (p.A313T) alteration is located in exon 3 (coding exon 3) of the PML gene. This alteration results from a G to A substitution at nucleotide position 937, causing the alanine (A) at amino acid position 313 to be replaced by a threonine (T). 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	Benign	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;.;.;.;T;.;.;.;.;.;.;.;.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;T;.;.;T;T;T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L;L;L;L;L;L;L;L;L;L;L;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	D;D;N;N;N;N;N;D;D;D;D;D;D;D
REVEL	Benign	0.066
Sift	Benign	0.091	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.14	B;.;P;P;P;B;.;B;B;B;P;B;B;.
Vest4		0.12
MutPred		0.31		Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);Gain of phosphorylation at A313 (P = 0.0637);
MVP		0.38
MPC		1.2
ClinPred		0.27	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.056
gMVP		0.53

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: chr15-74315503;