10-110887846-A-G

Variant names:

• chr10-110887846-A-G
• rs754289029
• NM_014456.5:c.737A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014456.5(PDCD4):​c.737A>G​(p.Asp246Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D246V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PDCD4 NM_014456.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.87
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37276745).

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.737A>G	p.Asp246Gly	missense	Exon 6 of 12	NP_055271.2
	PDCD4	NM_145341.4		c.704A>G	p.Asp235Gly	missense	Exon 7 of 13	NP_663314.1	Q53EL6-2
	PDCD4	NM_001199492.2		c.695A>G	p.Asp232Gly	missense	Exon 6 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.737A>G	p.Asp246Gly	missense	Exon 6 of 12	ENSP00000280154.7	Q53EL6-1
	PDCD4	ENST00000393104.6	TSL:1	c.704A>G	p.Asp235Gly	missense	Exon 7 of 13	ENSP00000376816.2	Q53EL6-2
	PDCD4	ENST00000888009.1		c.737A>G	p.Asp246Gly	missense	Exon 6 of 13	ENSP00000558068.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461062 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726856

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111372

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		8.9
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.23
Sift	Uncertain	0.021	D
Sift4G	Benign	0.15	T
Polyphen		0.052	B
Vest4		0.52
MutPred		0.43		Gain of loop (P = 0.0851)
MVP		0.41
MPC		0.31
ClinPred		0.96	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.46
gMVP		0.40
Mutation Taster		=32/68	disease causing

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: rs754289029; hg19: chr10-112647604;