chr15-74035775-A-C

Variant names:

• chr15-74035775-A-C
• rs743580
• ENST00000268059.10:c.2314A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033239.3(PML):​c.2314A>C​(p.Ser772Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/17 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. S772G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PML NM_033239.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.145
• Publications: 41 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05649072).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033239.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PML	NM_033238.3	MANE Select	c.1710+1245A>C		intron	N/A	NP_150241.2
	PML	NM_033239.3		c.2314A>C	p.Ser772Arg	missense	Exon 8 of 8	NP_150242.1
	PML	NM_033250.3		c.2170A>C	p.Ser724Arg	missense	Exon 7 of 7	NP_150253.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PML	ENST00000268059.10	TSL:1	c.2314A>C	p.Ser772Arg	missense	Exon 8 of 8	ENSP00000268059.6
	PML	ENST00000354026.10	TSL:1	c.2170A>C	p.Ser724Arg	missense	Exon 7 of 7	ENSP00000315434.8
	PML	ENST00000435786.6	TSL:1	c.*1119A>C		3_prime_UTR	Exon 7 of 7	ENSP00000395576.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.3
DANN	Benign	0.91
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.14
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.020
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.057	T
Polyphen		0.073	B
Vest4		0.14
MutPred		0.13		Gain of helix (P = 0.027)
MVP		0.13
ClinPred		0.11	T
GERP RS		0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs743580; hg19: chr15-74328116;