NM_033238.3:c.250T>G

Variant names:

• chr15-73998124-T-G
• rs752972084
• NM_033238.3:c.250T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_033238.3(PML):​c.250T>G​(p.Ser84Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: PML NM_033238.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.639
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.063577324).
• BS2: High AC in GnomAd4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033238.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PML	NM_033238.3	MANE Select	c.250T>G	p.Ser84Ala	missense	Exon 2 of 9	NP_150241.2	P29590-1
	PML	NM_033239.3		c.250T>G	p.Ser84Ala	missense	Exon 2 of 8	NP_150242.1	P29590-8
	PML	NM_033250.3		c.250T>G	p.Ser84Ala	missense	Exon 2 of 7	NP_150253.2	P29590-13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PML	ENST00000268058.8	TSL:1 MANE Select	c.250T>G	p.Ser84Ala	missense	Exon 2 of 9	ENSP00000268058.3	P29590-1
	PML	ENST00000565898.5	TSL:1	c.250T>G	p.Ser84Ala	missense	Exon 2 of 8	ENSP00000455838.1	P29590-11
	PML	ENST00000268059.10	TSL:1	c.250T>G	p.Ser84Ala	missense	Exon 2 of 8	ENSP00000268059.6	P29590-8

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 250828 AF XY: 0.0000442

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000138 AC: 201 AN: 1461686 Hom.: 0 Cov.: 32 AF XY: 0.000127 AC XY: 92 AN XY: 727152

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.000176 AC: 196 AN: 1111992

Other (OTH) AF: 0.0000331 AC: 2 AN: 60380

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

African (AFR) AF: 0.0000482 AC: 2 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.4
DANN	Benign	0.65
DEOGEN2	Benign	0.37	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		-0.64
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.032
Sift	Benign	0.77	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.58		Loss of glycosylation at S84 (P = 0.0135)
MVP		0.29
MPC		0.70
ClinPred		0.0062	T
GERP RS		-0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.31
gMVP		0.075
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752972084; hg19: chr15-74290465;