Genetic Variant CPEB3:p.Thr458Ile (chr10-92143109-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014912.5(CPEB3):c.1373C>T(p.Thr458Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CPEB3
NM_014912.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

CPEB3 (HGNC:21746): (cytoplasmic polyadenylation element binding protein 3) Enables mRNA 3'-UTR binding activity and translation factor activity, RNA binding. Involved in cellular response to amino acid stimulus; negative regulation of transcription by RNA polymerase II; and positive regulation of mRNA catabolic process. Located in several cellular components, including cytosol; midbody; and nucleoplasm. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Apr 2022]

CPEB3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPEB3	NM_014912.5 link	c.1373C>T	p.Thr458Ile	missense_variant	Exon 6 of 10	ENST00000265997.5	NP_055727.3	Q8NE35-1B3KXC1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CPEB3	ENST00000265997.5 link	c.1373C>T	p.Thr458Ile	missense_variant	Exon 6 of 10	1	NM_014912.5	ENSP00000265997.4	Q8NE35-1
CPEB3	ENST00000412050.8 link	c.1331C>T	p.Thr444Ile	missense_variant	Exon 6 of 10	1		ENSP00000398310.2	Q8NE35-2
CPEB3	ENST00000614585.4 link	c.1373C>T	p.Thr458Ile	missense_variant	Exon 6 of 10	5		ENSP00000482128.1	Q8NE35-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248254

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

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:

6.85e-7

AC:

AN:

1460166

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726402

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1373C>T (p.T458I) alteration is located in exon 6 (coding exon 5) of the CPEB3 gene. This alteration results from a C to T substitution at nucleotide position 1373, causing the threonine (T) at amino acid position 458 to be replaced by an isoleucine (I). 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

0.98

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

.;T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;.

M_CAP

Benign

0.015

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

.;L;L

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.5

D;.;D

REVEL

Uncertain

0.44

Sift

Benign

0.080

T;.;T

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.89

MutPred

0.42

.;Loss of glycosylation at T458 (P = 0.0535);Loss of glycosylation at T458 (P = 0.0535);

MVP

0.57

MPC

1.6

ClinPred

0.92

GERP RS

5.9

Varity_R

0.57

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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