Genetic Variant NM_016207.4:c.1438C>T (chr2-9452955-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016207.4(CPSF3):c.1438C>T(p.Arg480Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,610,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R480Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

CPSF3
NM_016207.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.50

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

CPSF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016207.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPSF3	NM_016207.4	MANE Select	c.1438C>T	p.Arg480Trp	missense	Exon 12 of 18	NP_057291.1	Q9UKF6
CPSF3	NM_001321836.2		c.1450C>T	p.Arg484Trp	missense	Exon 13 of 19	NP_001308765.1
CPSF3	NM_001321833.2		c.1327C>T	p.Arg443Trp	missense	Exon 12 of 18	NP_001308762.1	G5E9W3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPSF3	ENST00000238112.8	TSL:1 MANE Select	c.1438C>T	p.Arg480Trp	missense	Exon 12 of 18	ENSP00000238112.3	Q9UKF6
CPSF3	ENST00000460593.1	TSL:1	c.1327C>T	p.Arg443Trp	missense	Exon 12 of 18	ENSP00000418957.1	G5E9W3
CPSF3	ENST00000882814.1		c.1438C>T	p.Arg480Trp	missense	Exon 12 of 19	ENSP00000552873.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152060

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000483

AC:

AN:

248280

AF XY:

0.0000373

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000495

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000891

AC:

AN:

1458762

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725524

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000300

AC:

AN:

33296

American (AMR)

AF:

0.00

AC:

AN:

44068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.000177

AC:

AN:

39654

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111150

Other (OTH)

AF:

0.0000166

AC:

AN:

60268

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000645519), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.383

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000192

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

0.0082

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

1.0

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.4

PhyloP100

3.5

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.27

Sift

Uncertain

0.017

Sift4G

Uncertain

0.042

Polyphen

0.99

Vest4

0.93

MutPred

0.50

Loss of disorder (P = 0.0205)

MVP

0.76

MPC

1.2

ClinPred

0.90

GERP RS

5.9

Varity_R

0.66

gMVP

0.74

Mutation Taster

=41/59

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over