Genetic Variant CPSF3:p.Arg480Gln (chr2-9452956-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_016207.4(CPSF3):c.1439G>A(p.Arg480Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,140 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CPSF3
NM_016207.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.79

Variant links:

Genes affected

CPSF3 (HGNC:2326): (cleavage and polyadenylation specific factor 3) This gene encodes a member of the metallo-beta-lactamase family. The encoded protein is a 73kDa subunit of the cleavage and polyadenylation specificity factor and functions as an endonuclease that recognizes the pre-mRNA 3'-cleavage site AAUAAA prior to polyadenylation. It also cleaves after the pre-mRNA sequence ACCCA during histone 3'-end pre-mRNA processing. [provided by RefSeq, Oct 2012]

CPSF3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPSF3	NM_016207.4 link	c.1439G>A	p.Arg480Gln	missense_variant	Exon 12 of 18	ENST00000238112.8	NP_057291.1	Q9UKF6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPSF3	ENST00000238112.8 link	c.1439G>A	p.Arg480Gln	missense_variant	Exon 12 of 18	1	NM_016207.4	ENSP00000238112.3		Q9UKF6
CPSF3	ENST00000460593.1 link	c.1328G>A	p.Arg443Gln	missense_variant	Exon 12 of 18	1		ENSP00000418957.1		G5E9W3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248544

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134268

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS 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:

0.00000411

AC:

AN:

1459140

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725680

show subpopulations

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:

0.00000360

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1439G>A (p.R480Q) alteration is located in exon 12 (coding exon 12) of the CPSF3 gene. This alteration results from a G to A substitution at nucleotide position 1439, causing the arginine (R) at amino acid position 480 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

Benign

0.12

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

T;.

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.26

N;N

REVEL

Benign

0.20

Sift

Benign

0.59

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.012

B;.

Vest4

0.87

MutPred

0.54

Loss of MoRF binding (P = 0.0475);.;

MVP

0.60

MPC

0.52

ClinPred

0.65

GERP RS

5.9

Varity_R

0.18

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over