11-83165623-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001346413.3(PCF11):c.726G>C(p.Gln242His) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCF11 NM_001346413.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.190

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.163212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCF11	NM_001346413.3	c.726G>C	p.Gln242His	missense_variant	5/16	ENST00000690938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCF11	ENST00000690938.1	c.726G>C	p.Gln242His	missense_variant	5/16		NM_001346413.3	P3
PCF11	ENST00000298281.8	c.726G>C	p.Gln242His	missense_variant	5/16	1		A1
PCF11	ENST00000530304.5	c.726G>C	p.Gln242His	missense_variant	5/8	1
PCF11	ENST00000530660.5	c.726G>C	p.Gln242His	missense_variant	5/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jan 03, 2024

The c.726G>C (p.Q242H) alteration is located in exon 5 (coding exon 5) of the PCF11 gene. This alteration results from a G to C substitution at nucleotide position 726, causing the glutamine (Q) at amino acid position 242 to be replaced by a histidine (H). 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	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.026	T;T;.
Eigen	Benign	0.025
Eigen_PC	Benign	0.024
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	0.69	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.045	D;D;D
Sift4G	Benign	0.090	T;T;T
Polyphen		0.95	P;D;.
Vest4		0.30
MutPred		0.15		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.59
MPC		0.34
ClinPred		0.59	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.46

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-82876665;