rs1178944366

Variant names:

• chr15-74022857-T-A
• rs1178944366
• NM_033238.3:c.632T>A

Your query was ambiguous. Multiple possible variants found:

• chr15-74022857-T-A
• chr15-74022857-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_033238.3(PML):​c.632T>A​(p.Leu211Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PML NM_033238.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78
• 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 -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• BS2: High AC in GnomAdExome4 at 11 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.632T>A	p.Leu211Gln	missense	Exon 3 of 9	NP_150241.2	P29590-1
	PML	NM_033239.3		c.632T>A	p.Leu211Gln	missense	Exon 3 of 8	NP_150242.1	P29590-8
	PML	NM_033250.3		c.632T>A	p.Leu211Gln	missense	Exon 3 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.632T>A	p.Leu211Gln	missense	Exon 3 of 9	ENSP00000268058.3	P29590-1
	PML	ENST00000565898.5	TSL:1	c.632T>A	p.Leu211Gln	missense	Exon 3 of 8	ENSP00000455838.1	P29590-11
	PML	ENST00000268059.10	TSL:1	c.632T>A	p.Leu211Gln	missense	Exon 3 of 8	ENSP00000268059.6	P29590-8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 249862 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461596 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727090

African (AFR) AF: 0.000119 AC: 4 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111962

Other (OTH) AF: 0.0000497 AC: 3 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.8
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.68		Gain of disorder (P = 0.0551)
MVP		0.86
MPC		2.0
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.95
Mutation Taster		=82/18	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: rs1178944366; hg19: chr15-74315198;