chr15-73998239-T-C

Position:

• chr15-73998239-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_033238.3(PML):​c.365T>C​(p.Ile122Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PML NM_033238.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40775502).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PML	NM_033238.3	c.365T>C	p.Ile122Thr	missense_variant	2/9	ENST00000268058.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PML	ENST00000268058.8	c.365T>C	p.Ile122Thr	missense_variant	2/9	1	NM_033238.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249452 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135072

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

Dec 28, 2023

The c.365T>C (p.I122T) alteration is located in exon 2 (coding exon 2) of the PML gene. This alteration results from a T to C substitution at nucleotide position 365, causing the isoleucine (I) at amino acid position 122 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	Pathogenic	0.64
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Uncertain	0.77	.;.;.;.;D;.;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;.;.;D;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.4	M;M;M;M;M;M;M;M;M;M;M;M;M;.
MutationTaster	Benign	0.52	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D;D;T;T;T;T;T;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		0.34	B;.;D;D;D;D;.;D;D;D;D;P;D;.
Vest4		0.28
MutPred		0.56		Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);
MVP		0.58
MPC		2.0
ClinPred		0.89	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.39

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: rs758491320; hg19: chr15-74290580;