chr15-74022857-T-C

Variant names:

• chr15-74022857-T-C
• NM_033238.3:c.632T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033238.3(PML):​c.632T>C​(p.Leu211Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PML NM_033238.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PML	NM_033238.3	c.632T>C	p.Leu211Pro	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.632T>C	p.Leu211Pro	missense_variant	Exon 3 of 9	1	NM_033238.3	ENSP00000268058.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461596 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727090

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;.;.;.;D;.;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;.;.;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.3	M;M;M;M;M;M;M;M;M;M;M;M;M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.52
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		0.92
MutPred		0.75		Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);Gain of catalytic residue at P210 (P = 0.0184);
MVP		0.90
MPC		2.5
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.97

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: chr15-74315198;