11-83165781-G-A

Variant names:

• chr11-83165781-G-A
• rs1322320178
• NM_001346413.3:c.884G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001346413.3(PCF11):​c.884G>A​(p.Arg295Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,426 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PCF11 NM_001346413.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.70

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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCF11	NM_001346413.3	c.884G>A	p.Arg295Gln	missense_variant	Exon 5 of 16	ENST00000690938.1	NP_001333342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCF11	ENST00000690938.1	c.884G>A	p.Arg295Gln	missense_variant	Exon 5 of 16		NM_001346413.3	ENSP00000508500.1
PCF11	ENST00000298281.8	c.884G>A	p.Arg295Gln	missense_variant	Exon 5 of 16	1		ENSP00000298281.4
PCF11	ENST00000530304.5	c.884G>A	p.Arg295Gln	missense_variant	Exon 5 of 8	1		ENSP00000431567.1
PCF11	ENST00000530660.5	c.884G>A	p.Arg295Gln	missense_variant	Exon 5 of 8	2		ENSP00000434540.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000812 AC: 2 AN: 246344 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133598

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460426 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726344

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.884G>A (p.R295Q) alteration is located in exon 5 (coding exon 5) of the PCF11 gene. This alteration results from a G to A substitution at nucleotide position 884, causing the arginine (R) at amino acid position 295 to be replaced by a glutamine (Q). 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	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.027	T;T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.0	N;D;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.63
MutPred		0.19		Loss of MoRF binding (P = 0.0262);Loss of MoRF binding (P = 0.0262);Loss of MoRF binding (P = 0.0262);
MVP		0.84
MPC		0.77
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.28
gMVP		0.34

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: rs1322320178; hg19: chr11-82876823; COSMIC: COSV53538266; COSMIC: COSV53538266;