11-83165894-A-C

Position:

• chr11-83165894-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001346413.3(PCF11):​c.997A>C​(p.Ile333Leu) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCF11 NM_001346413.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.687

Genes affected

PCF11 (HGNC:30097): (PCF11 cleavage and polyadenylation factor subunit) The protein encoded by this gene binds to CLP1 to form pre-mRNA cleavage factor IIm. The encoded protein is necessary for efficient Pol II transcription termination and may be involved in degradation of the 3' product of polyA site cleavage. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03432861).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCF11	NM_001346413.3	c.997A>C	p.Ile333Leu	missense_variant	5/16	ENST00000690938.1	NP_001333342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCF11	ENST00000690938.1	c.997A>C	p.Ile333Leu	missense_variant	5/16		NM_001346413.3	ENSP00000508500.1
PCF11	ENST00000298281.8	c.997A>C	p.Ile333Leu	missense_variant	5/16	1		ENSP00000298281.4
PCF11	ENST00000530304.5	c.997A>C	p.Ile333Leu	missense_variant	5/8	1		ENSP00000431567.1
PCF11	ENST00000530660.5	c.997A>C	p.Ile333Leu	missense_variant	5/8	2		ENSP00000434540.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2024

The c.997A>C (p.I333L) alteration is located in exon 5 (coding exon 5) of the PCF11 gene. This alteration results from a A to C substitution at nucleotide position 997, causing the isoleucine (I) at amino acid position 333 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.8
DANN	Benign	0.81
DEOGEN2	Benign	0.0055	T;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.51	T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.47	N;N;N
REVEL	Benign	0.063
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.10
MutPred		0.15		Loss of methylation at K328 (P = 0.1396);Loss of methylation at K328 (P = 0.1396);Loss of methylation at K328 (P = 0.1396);
MVP		0.15
MPC		0.17
ClinPred		0.086	T
GERP RS		1.5
Varity_R		0.037
gMVP		0.036

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: rs1013226559; hg19: chr11-82876936;