15-73994894-A-C

Position:

• chr15-73994894-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_033238.3(PML):​c.82A>C​(p.Thr28Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,546,602 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (20 hom.)
• Consequence: PML NM_033238.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.12

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024793148).
• BP6: Variant 15-73994894-A-C is Benign according to our data. Variant chr15-73994894-A-C is described in ClinVar as [Benign]. Clinvar id is 776928.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00804 (1211/150560) while in subpopulation AFR AF= 0.028 (1145/40828). AF 95% confidence interval is 0.0267. There are 18 homozygotes in gnomad4. There are 586 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1211 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PML	NM_033238.3	c.82A>C	p.Thr28Pro	missense_variant	1/9	ENST00000268058.8	NP_150241.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PML	ENST00000268058.8	c.82A>C	p.Thr28Pro	missense_variant	1/9	1	NM_033238.3	ENSP00000268058	P1

Frequencies

GnomAD3 genomes AF: 0.00804 AC: 1209 AN: 150460 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00285

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00485

GnomAD3 exomes AF: 0.00161 AC: 245 AN: 152548 Hom.: 3 AF XY: 0.00148 AC XY: 121 AN XY: 81976

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.000876

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000864

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.000824 AC: 1150 AN: 1396042 Hom.: 20 Cov.: 32 AF XY: 0.000774 AC XY: 533 AN XY: 689064

Gnomad4 AFR exome AF: 0.0286

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000378

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000818

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00804 AC: 1211 AN: 150560 Hom.: 18 Cov.: 32 AF XY: 0.00797 AC XY: 586 AN XY: 73536

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00284

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000213

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000163

Gnomad4 OTH AF: 0.00480

Alfa AF: 0.00264 Hom.: 3

Bravo AF: 0.00915

ESP6500AA AF: 0.00248 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000645 AC: 65

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.056
DANN	Benign	0.68
DEOGEN2	Benign	0.28	.;.;.;.;T;.;.;.;.;.;.;.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.49	T;T;T;T;T;T;T;.;.;T;T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N;N;N;N;N;N;N;N;N;N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.60	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;.;B;B;B;B;.;B;B;B;B;B;B;.
Vest4		0.088
MVP		0.26
MPC		1.1
ClinPred		0.0038	T
GERP RS		-4.5
Varity_R		0.12
gMVP		0.13

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: rs28504405; hg19: chr15-74287235;