chr19-10457992-C-T

Variant names:

• chr19-10457992-C-T
• rs150660796
• NM_001111307.2:c.991C>T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 2.35
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 438 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111307.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4A	NM_001111307.2	MANE Select	c.991C>T	p.Pro331Ser	missense	Exon 8 of 15	NP_001104777.1
	PDE4A	NM_001243121.2		c.925C>T	p.Pro309Ser	missense	Exon 10 of 17	NP_001230050.1
	PDE4A	NM_001111308.1		c.913C>T	p.Pro305Ser	missense	Exon 8 of 15	NP_001104778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4A	ENST00000380702.7	TSL:1 MANE Select	c.991C>T	p.Pro331Ser	missense	Exon 8 of 15	ENSP00000370078.3
	PDE4A	ENST00000592685.5	TSL:1	c.925C>T	p.Pro309Ser	missense	Exon 10 of 17	ENSP00000468507.1
	PDE4A	ENST00000293683.9	TSL:1	c.913C>T	p.Pro305Ser	missense	Exon 8 of 15	ENSP00000293683.4

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

GnomAD2 exomes AF: 0.00458 AC: 1147 AN: 250660 AF XY: 0.00349

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 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

African (AFR) AF: 0.000747 AC: 25 AN: 33478

American (AMR) AF: 0.0330 AC: 1476 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00124 AC: 107 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111982

Other (OTH) AF: 0.00142 AC: 86 AN: 60394

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

African (AFR) AF: 0.00135 AC: 56 AN: 41540

American (AMR) AF: 0.0237 AC: 362 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000648 Hom.: 1

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 20, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0081	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.4
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.21
Sift	Benign	0.13	T
Sift4G	Benign	0.087	T
Polyphen		0.23	B
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
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs150660796; hg19: chr19-10568668;