10-110895964-A-G

Variant names:

• chr10-110895964-A-G
• NM_014456.5:c.1226A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014456.5(PDCD4):​c.1226A>G​(p.Tyr409Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: PDCD4 NM_014456.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

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.1226A>G	p.Tyr409Cys	missense	Exon 11 of 12	NP_055271.2
	PDCD4	NM_145341.4		c.1193A>G	p.Tyr398Cys	missense	Exon 12 of 13	NP_663314.1	Q53EL6-2
	PDCD4	NM_001199492.2		c.1184A>G	p.Tyr395Cys	missense	Exon 11 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.1226A>G	p.Tyr409Cys	missense	Exon 11 of 12	ENSP00000280154.7	Q53EL6-1
	PDCD4	ENST00000393104.6	TSL:1	c.1193A>G	p.Tyr398Cys	missense	Exon 12 of 13	ENSP00000376816.2	Q53EL6-2
	PDCD4	ENST00000888009.1		c.1226A>G	p.Tyr409Cys	missense	Exon 11 of 13	ENSP00000558068.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

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	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		8.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.61		Loss of phosphorylation at Y409 (P = 0.0483)
MVP		0.78
MPC		0.50
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.85
gMVP		0.78
Mutation Taster		=13/87	disease causing

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

Other links and lift over

hg19: chr10-112655722;