Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016953.4(PDE11A):c.2632A>G(p.Met878Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,589,640 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 7 hom., cov: 32)

Exomes 𝑓: 0.011 ( 132 hom. )

Consequence

PDE11A
NM_016953.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.45

Publications

23 publications found

Variant links:

Genes affected

PDE11A (HGNC:8773): (phosphodiesterase 11A) The 3',5'-cyclic nucleotides cAMP and cGMP function as second messengers in a wide variety of signal transduction pathways. 3',5'-cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP to the corresponding 5'-monophosphates and provide a mechanism to downregulate cAMP and cGMP signaling. This gene encodes a member of the PDE protein superfamily. Mutations in this gene are a cause of Cushing disease and adrenocortical hyperplasia. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PDE11A links:

PDE11A-AS1 (HGNC:40433): (PDE11A antisense RNA 1)

PDE11A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020577222).

BP6

Variant 2-177663880-T-C is Benign according to our data. Variant chr2-177663880-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00677 (1032/152328) while in subpopulation NFE AF = 0.0119 (810/68038). AF 95% confidence interval is 0.0112. There are 7 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1032 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016953.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PDE11A	NM_016953.4	MANE Select	c.2632A>G	p.Met878Val	missense	Exon 19 of 20	NP_058649.3
PDE11A	NM_001077197.2		c.1882A>G	p.Met628Val	missense	Exon 20 of 21	NP_001070665.1
PDE11A	NM_001077358.2		c.1558A>G	p.Met520Val	missense	Exon 18 of 19	NP_001070826.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PDE11A	ENST00000286063.11	TSL:1 MANE Select	c.2632A>G	p.Met878Val	missense	Exon 19 of 20	ENSP00000286063.5
PDE11A	ENST00000358450.8	TSL:1	c.1882A>G	p.Met628Val	missense	Exon 20 of 21	ENSP00000351232.4
PDE11A	ENST00000409504.5	TSL:1	c.1558A>G	p.Met520Val	missense	Exon 18 of 20	ENSP00000386539.1

Frequencies

GnomAD3 genomes

AF:

0.00678

AC:

1032

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00236

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00655

AC:

1645

AN:

251106

AF XY:

0.00664

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00544

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00314

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.00800

GnomAD4 exome

AF:

0.0110

AC:

15750

AN:

1437312

Hom.:

132

Cov.:

AF XY:

0.0106

AC XY:

7618

AN XY:

716870

show subpopulations

African (AFR)

AF:

0.00206

AC:

AN:

32982

American (AMR)

AF:

0.00551

AC:

246

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00242

AC:

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

AN:

39576

South Asian (SAS)

AF:

0.00170

AC:

146

AN:

85772

European-Finnish (FIN)

AF:

0.00320

AC:

171

AN:

53402

Middle Eastern (MID)

AF:

0.000700

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0133

AC:

14438

AN:

1089568

Other (OTH)

AF:

0.0103

AC:

614

AN:

59616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

663

1326

1989

2652

3315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

554

1108

1662

2216

2770

<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:

0.00677

AC:

1032

AN:

152328

Hom.:

Cov.:

AF XY:

0.00595

AC XY:

443

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41562

American (AMR)

AF:

0.00359

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00124

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00433

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

810

AN:

68038

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00916

Hom.:

Bravo

AF:

0.00693

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0133

AC:

114

ExAC

AF:

0.00649

AC:

788

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0119

EpiControl

AF:

0.0111

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.16

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.53

PhyloP100

1.4

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.3

REVEL

Benign

0.16

Sift

Uncertain

0.028

Sift4G

Benign

0.071

Polyphen

0.027

Vest4

0.64

MVP

0.68

MPC

0.19

ClinPred

0.0061

GERP RS

3.7

Varity_R

0.18

gMVP

0.39

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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rs74357545

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over