15-74022857-T-A

Position:

• chr15-74022857-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_033238.3(PML):​c.632T>A​(p.Leu211Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PML NM_033238.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PML	NM_033238.3	c.632T>A	p.Leu211Gln	missense_variant	3/9	ENST00000268058.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PML	ENST00000268058.8	c.632T>A	p.Leu211Gln	missense_variant	3/9	1	NM_033238.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461596 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727090

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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 06, 2022

The c.632T>A (p.L211Q) alteration is located in exon 3 (coding exon 3) of the PML gene. This alteration results from a T to A substitution at nucleotide position 632, causing the leucine (L) at amino acid position 211 to be replaced by a glutamine (Q). 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	0.72
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;.;.;D;.;.;.;.;.;.;.;.;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;.;.;D;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.3	M;M;M;M;M;M;M;M;M;M;M;M;M;.
MutationTaster	Benign	0.64	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D;.;D;D;D;D;D;D;.
Vest4		0.85
MutPred		0.68		Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);Gain of disorder (P = 0.0551);
MVP		0.86
MPC		2.0
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
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

LitVar

Other links and lift over

dbSNP: rs1178944366; hg19: chr15-74315198;