NM_014456.5:c.1132A>G

Variant names:

• chr10-110894445-A-G
• rs766888430
• NM_014456.5:c.1132A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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. 14/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13908899).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014456.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD4	NM_014456.5	MANE Select	c.1132A>G	p.Ser378Gly	missense	Exon 10 of 12	NP_055271.2
	PDCD4	NM_145341.4		c.1099A>G	p.Ser367Gly	missense	Exon 11 of 13	NP_663314.1	Q53EL6-2
	PDCD4	NM_001199492.2		c.1090A>G	p.Ser364Gly	missense	Exon 10 of 12	NP_001186421.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDCD4	ENST00000280154.12	TSL:1 MANE Select	c.1132A>G	p.Ser378Gly	missense	Exon 10 of 12	ENSP00000280154.7	Q53EL6-1
	PDCD4	ENST00000393104.6	TSL:1	c.1099A>G	p.Ser367Gly	missense	Exon 11 of 13	ENSP00000376816.2	Q53EL6-2
	PDCD4	ENST00000888009.1		c.1132A>G	p.Ser378Gly	missense	Exon 10 of 13	ENSP00000558068.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249304 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1420516 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 709276

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

African (AFR) AF: 0.00 AC: 0 AN: 32666

American (AMR) AF: 0.0000225 AC: 1 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25780

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39356

South Asian (SAS) AF: 0.00 AC: 0 AN: 85218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075702

Other (OTH) AF: 0.00 AC: 0 AN: 59050

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.16	N
PhyloP100		5.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.061
Sift	Benign	0.34	T
Sift4G	Benign	0.39	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	T
GERP RS		5.8
Varity_R		0.28
gMVP		0.13
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs766888430; hg19: chr10-112654203;