Genetic Variant CPSF3:p.Lys473Arg (chr2-9452935-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_016207.4(CPSF3):c.1418A>G(p.Lys473Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 1,602,796 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0044 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0064 ( 47 hom. )

Consequence

CPSF3
NM_016207.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.58

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009083629).

BP6

Variant 2-9452935-A-G is Benign according to our data. Variant chr2-9452935-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2650663.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPSF3	NM_016207.4 link	c.1418A>G	p.Lys473Arg	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.1418A>G	p.Lys473Arg	missense_variant	Exon 12 of 18	1	NM_016207.4	ENSP00000238112.3		Q9UKF6
CPSF3	ENST00000460593.1 link	c.1307A>G	p.Lys436Arg	missense_variant	Exon 12 of 18	1		ENSP00000418957.1		G5E9W3

Frequencies

GnomAD3 genomes

AF:

0.00436

AC:

664

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00647

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00484

AC:

1162

AN:

239876

Hom.:

AF XY:

0.00500

AC XY:

648

AN XY:

129524

show subpopulations

Gnomad AFR exome

AF:

0.00125

Gnomad AMR exome

AF:

0.00566

Gnomad ASJ exome

AF:

0.0161

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00177

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00642

Gnomad OTH exome

AF:

0.00786

GnomAD4 exome

AF:

0.00637

AC:

9238

AN:

1450472

Hom.:

Cov.:

AF XY:

0.00625

AC XY:

4508

AN XY:

721128

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00577

Gnomad4 ASJ exome

AF:

0.0156

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00189

Gnomad4 FIN exome

AF:

0.000469

Gnomad4 NFE exome

AF:

0.00706

Gnomad4 OTH exome

AF:

0.00769

GnomAD4 genome

AF:

0.00435

AC:

663

AN:

152324

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

319

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.00490

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00647

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.00653

Hom.:

Bravo

AF:

0.00505

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.00448

AC:

544

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00889

EpiControl

AF:

0.00877

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CPSF3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.0092

MetaRNN

Benign

0.0091

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

L;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.065

Sift

Benign

0.17

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.0

B;.

Vest4

0.27

MVP

0.53

MPC

0.36

ClinPred

0.015

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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