NM_001098818.4:c.1327G>T

Variant names:

• chr19-18216803-C-A
• rs746162922
• NM_001098818.4:c.1327G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001098818.4(PDE4C):​c.1327G>T​(p.Asp443Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D443N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PDE4C NM_001098818.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.81
• Publications: 0 publications found

Genes affected

PDE4C (HGNC:8782): (phosphodiesterase 4C) The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE4 subfamily. This PDE hydrolyzes the second messenger, cAMP, which is a regulator and mediator of a number of cellular responses to extracellular signals. Thus, by regulating the cellular concentration of cAMP, this protein plays a key role in many important physiological processes. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Jul 2011]

PDE4C (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098818.4. 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
	PDE4C	NM_001098818.4	MANE Select	c.1327G>T	p.Asp443Tyr	missense	Exon 12 of 15	NP_001092288.1	Q08493-3
	PDE4C	NM_000923.6		c.1423G>T	p.Asp475Tyr	missense	Exon 13 of 16	NP_000914.2	Q08493-1
	PDE4C	NM_001330172.2		c.1423G>T	p.Asp475Tyr	missense	Exon 13 of 16	NP_001317101.1	Q08493-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4C	ENST00000262805.17	TSL:1 MANE Select	c.1327G>T	p.Asp443Tyr	missense	Exon 12 of 15	ENSP00000262805.10	Q08493-3
	PDE4C	ENST00000355502.7	TSL:2	c.1423G>T	p.Asp475Tyr	missense	Exon 16 of 19	ENSP00000347689.2
	PDE4C	ENST00000594465.7	TSL:1	c.1423G>T	p.Asp475Tyr	missense	Exon 12 of 15	ENSP00000470210.1	Q08493-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459602 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726024

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53032

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110658

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		3.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-8.3	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.75		Gain of catalytic residue at Q478 (P = 0.0289)
MVP		0.84
MPC		1.3
ClinPred		1.0	D
GERP RS		2.4
Varity_R		0.90
gMVP		0.88
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs746162922; hg19: chr19-18327613; COSMIC: COSV53208687; COSMIC: COSV53208687;