Genetic Variant PDCD4:p.Ser378Gly (chr10-110894445-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014456.5(PDCD4):c.1132A>G(p.Ser378Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,420,516 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PDCD4
NM_014456.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.58

Variant links:

Genes affected

PDCD4 (HGNC:8763): (programmed cell death 4) This gene is a tumor suppressor and encodes a protein that binds to the eukaryotic translation initiation factor 4A1 and inhibits its function by preventing RNA binding. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]

PDCD4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13908899).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDCD4	NM_014456.5 link	c.1132A>G	p.Ser378Gly	missense_variant	Exon 10 of 12	ENST00000280154.12	NP_055271.2	Q53EL6-1
PDCD4	NM_145341.4 link	c.1099A>G	p.Ser367Gly	missense_variant	Exon 11 of 13		NP_663314.1	Q53EL6-2
PDCD4	NM_001199492.2 link	c.1090A>G	p.Ser364Gly	missense_variant	Exon 10 of 12		NP_001186421.1	B4DKX4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDCD4	ENST00000280154.12 link	c.1132A>G	p.Ser378Gly	missense_variant	Exon 10 of 12	1	NM_014456.5	ENSP00000280154.7		Q53EL6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249304

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134926

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.00000141

AC:

AN:

1420516

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709276

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

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.:

Bravo

AF:

0.00000378

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

Jan 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1132A>G (p.S378G) alteration is located in exon 10 (coding exon 9) of the PDCD4 gene. This alteration results from a A to G substitution at nucleotide position 1132, causing the serine (S) at amino acid position 378 to be replaced by a glycine (G). 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

0.062

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.0045

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.16

.;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.061

Sift

Benign

0.34

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0

.;B

Vest4

0.22

MutPred

0.29

.;Gain of ubiquitination at K381 (P = 0.0831);

MVP

0.37

MPC

0.073

ClinPred

0.20

GERP RS

5.8

Varity_R

0.28

gMVP

0.13

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