Genetic Variant NM_001111307.2:c.741C>T (chr19-10450899-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_001111307.2(PDE4A):c.741C>T(p.Thr247Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,610,780 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 2 hom. )

Consequence

PDE4A
NM_001111307.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.183

Publications

1 publications found

Variant links:

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]

PDE4A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 19-10450899-C-T is Benign according to our data. Variant chr19-10450899-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2649292.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.183 with no splicing effect.

BS2

High AC in GnomAd4 at 233 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDE4A	NM_001111307.2	MANE Select	c.741C>T	p.Thr247Thr	synonymous	Exon 6 of 15	NP_001104777.1	P27815-1
PDE4A	NM_001243121.2		c.675C>T	p.Thr225Thr	synonymous	Exon 8 of 17	NP_001230050.1	P27815-7
PDE4A	NM_001111308.1		c.663C>T	p.Thr221Thr	synonymous	Exon 6 of 15	NP_001104778.1	P27815-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDE4A	ENST00000380702.7	TSL:1 MANE Select	c.741C>T	p.Thr247Thr	synonymous	Exon 6 of 15	ENSP00000370078.3	P27815-1
PDE4A	ENST00000592685.5	TSL:1	c.675C>T	p.Thr225Thr	synonymous	Exon 8 of 17	ENSP00000468507.1	P27815-7
PDE4A	ENST00000293683.9	TSL:1	c.663C>T	p.Thr221Thr	synonymous	Exon 6 of 15	ENSP00000293683.4	P27815-2

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

233

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00262

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00110

AC:

266

AN:

241532

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.000338

Gnomad AMR exome

AF:

0.000178

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00143

Gnomad NFE exome

AF:

0.00197

Gnomad OTH exome

AF:

0.00101

GnomAD4 exome

AF:

0.00189

AC:

2763

AN:

1458440

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

1368

AN XY:

725098

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33428

American (AMR)

AF:

0.000226

AC:

AN:

44214

Ashkenazi Jewish (ASJ)

AF:

0.000154

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.0000703

AC:

AN:

85392

European-Finnish (FIN)

AF:

0.00182

AC:

AN:

53216

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00228

AC:

2528

AN:

1110584

Other (OTH)

AF:

0.00178

AC:

107

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

152

304

456

608

760

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00153

AC:

233

AN:

152340

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41584

American (AMR)

AF:

0.000981

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00262

AC:

178

AN:

68026

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00227

Hom.:

Bravo

AF:

0.00141

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

0.18

PromoterAI

-0.0088

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over