rs150660796

chr19-10457992-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001111307.2(PDE4A):c.991C>T(p.Pro331Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,950 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (52 hom.)
• Consequence: PDE4A NM_001111307.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.35

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008137226).
• BP6: Variant 19-10457992-C-T is Benign according to our data. Variant chr19-10457992-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00288 (438/152256) while in subpopulation AMR AF= 0.0237 (362/15288). AF 95% confidence interval is 0.0217. There are 9 homozygotes in gnomad4. There are 221 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 429 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE4A	NM_001111307.2	c.991C>T	p.Pro331Ser	missense_variant	8/15	ENST00000380702.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE4A	ENST00000380702.7	c.991C>T	p.Pro331Ser	missense_variant	8/15	1	NM_001111307.2

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152138 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00458 AC: 1147 AN: 250660 Hom.: 28 AF XY: 0.00349 AC XY: 474 AN XY: 135776

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.0302

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.00426

GnomAD4 exome AF: 0.00118 AC: 1719 AN: 1461694 Hom.: 52 Cov.: 37 AF XY: 0.00104 AC XY: 753 AN XY: 727146

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.0330

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00288 AC: 438 AN: 152256 Hom.: 9 Cov.: 32 AF XY: 0.00297 AC XY: 221 AN XY: 74472

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.0237

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000385 Hom.: 0

Bravo AF: 0.00498

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00330 AC: 401

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 20, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
MetaRNN	Benign	0.0081	T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.48	T
Sift4G	Benign	0.087	T;T;T;T;T;T
Polyphen		0.23, 0.11, 1.0, 0.57	.;B;B;D;.;P
Vest4		0.38
MVP		0.79
ClinPred		0.028	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs150660796; hg19: chr19-10568668;