15-73994933-C-G

Variant names:

• chr15-73994933-C-G
• rs779135665
• NM_033238.3:c.121C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_033238.3(PML):​c.121C>G​(p.Pro41Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,544,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P41S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: PML NM_033238.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08089867).
• BS2: High AC in GnomAd4 at 12 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.121C>G	p.Pro41Ala	missense	Exon 1 of 9	NP_150241.2	P29590-1
	PML	NM_033239.3		c.121C>G	p.Pro41Ala	missense	Exon 1 of 8	NP_150242.1	P29590-8
	PML	NM_033250.3		c.121C>G	p.Pro41Ala	missense	Exon 1 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.121C>G	p.Pro41Ala	missense	Exon 1 of 9	ENSP00000268058.3	P29590-1
	PML	ENST00000565898.5	TSL:1	c.121C>G	p.Pro41Ala	missense	Exon 1 of 8	ENSP00000455838.1	P29590-11
	PML	ENST00000268059.10	TSL:1	c.121C>G	p.Pro41Ala	missense	Exon 1 of 8	ENSP00000268059.6	P29590-8

Frequencies

GnomAD3 genomes AF: 0.0000790 AC: 12 AN: 151988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000112 AC: 16 AN: 142778 AF XY: 0.000117

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000423

Gnomad ASJ exome AF: 0.000774

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000952

Gnomad OTH exome AF: 0.000736

GnomAD4 exome AF: 0.000103 AC: 143 AN: 1392434 Hom.: 0 Cov.: 33 AF XY: 0.000111 AC XY: 76 AN XY: 686426

African (AFR) AF: 0.0000319 AC: 1 AN: 31318

American (AMR) AF: 0.000288 AC: 10 AN: 34668

Ashkenazi Jewish (ASJ) AF: 0.000729 AC: 18 AN: 24680

East Asian (EAS) AF: 0.00 AC: 0 AN: 35712

South Asian (SAS) AF: 0.000177 AC: 14 AN: 78884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48026

Middle Eastern (MID) AF: 0.000709 AC: 4 AN: 5640

European-Non Finnish (NFE) AF: 0.0000669 AC: 72 AN: 1075816

Other (OTH) AF: 0.000416 AC: 24 AN: 57690

GnomAD4 genome AF: 0.0000790 AC: 12 AN: 151988 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74232

African (AFR) AF: 0.00 AC: 0 AN: 41344

American (AMR) AF: 0.000459 AC: 7 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.0000359 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	0.084
Eigen_PC	Benign	-0.030
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.9
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.051
Sift	Uncertain	0.020	D
Sift4G	Benign	0.24	T
Polyphen		0.97	D
Vest4		0.14
MutPred		0.21		Loss of glycosylation at P41 (P = 0.0076)
MVP		0.74
MPC		1.4
ClinPred		0.30	T
GERP RS		2.9
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.16
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs779135665; hg19: chr15-74287274;