Genetic Variant NM_016207.4:c.1547C>T (chr2-9455701-C-T) – 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.1547C>T(p.Ala516Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CPSF3
NM_016207.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

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:

Genome browser will be placed here

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.1547C>T	p.Ala516Val	missense_variant	Exon 13 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.1547C>T	p.Ala516Val	missense_variant	Exon 13 of 18	1	NM_016207.4	ENSP00000238112.3		Q9UKF6
CPSF3	ENST00000460593.1 link	c.1436C>T	p.Ala479Val	missense_variant	Exon 13 of 18	1		ENSP00000418957.1		G5E9W3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727204

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:

0.0000144

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1547C>T (p.A516V) alteration is located in exon 13 (coding exon 13) of the CPSF3 gene. This alteration results from a C to T substitution at nucleotide position 1547, causing the alanine (A) at amino acid position 516 to be replaced by a valine (V). 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

0.33

BayesDel_addAF

Benign

0.0014

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.054

T;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.17

Sift

Benign

0.13

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.030

B;.

Vest4

0.72

MutPred

0.32

Loss of ubiquitination at K512 (P = 0.0901);.;

MVP

0.66

MPC

0.46

ClinPred

0.80

GERP RS

5.9

Varity_R

0.24

gMVP

0.66

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

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