rs376507621

Variant names:

• chr19-10457912-C-G
• NM_001111307.2:c.911C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-10457912-C-G
• chr19-10457912-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001111307.2(PDE4A):​c.911C>G​(p.Thr304Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. T304M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PDE4A NM_001111307.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.896

Genes affected

PDE4A (HGNC:8780): (phosphodiesterase 4A) 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]

ACMG classification

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=0.16979599).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE4A	NM_001111307.2	c.911C>G	p.Thr304Arg	missense_variant	Exon 8 of 15	ENST00000380702.7	NP_001104777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE4A	ENST00000380702.7	c.911C>G	p.Thr304Arg	missense_variant	Exon 8 of 15	1	NM_001111307.2	ENSP00000370078.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460356 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 726450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	.;T;.;.;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.3	.;L;.;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.8	.;.;D;D;.;D
REVEL	Benign	0.21
Sift	Benign	0.12	.;.;T;T;.;T
Sift4G	Benign	0.19	T;T;T;T;T;T
Polyphen		0.97, 0.36, 0.99, 0.99	.;D;B;D;.;D
Vest4		0.54
MutPred		0.24		.;Loss of glycosylation at T304 (P = 0.0099);.;.;.;.;
MVP		0.57
ClinPred		0.98	D
GERP RS		1.8
Varity_R		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10568588;