rs74357545

Variant names:

Your query was ambiguous. Multiple possible variants found:

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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE11A	NM_016953.4 link	c.2632A>G	p.Met878Val	missense_variant	Exon 19 of 20	ENST00000286063.11	NP_058649.3	Q9HCR9-1
PDE11A	NM_001077197.2 link	c.1882A>G	p.Met628Val	missense_variant	Exon 20 of 21		NP_001070665.1	Q9HCR9-2
PDE11A	NM_001077358.2 link	c.1558A>G	p.Met520Val	missense_variant	Exon 18 of 19		NP_001070826.1	Q9HCR9-3
PDE11A	NM_001077196.2 link	c.1300A>G	p.Met434Val	missense_variant	Exon 16 of 17		NP_001070664.1	Q9HCR9-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11 link	c.2632A>G	p.Met878Val	missense_variant	Exon 19 of 20	1	NM_016953.4	ENSP00000286063.5		Q9HCR9-1

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

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

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

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 30, 2016

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 v4.3

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

T;.;.;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.92

D;D;D;D

MetaRNN

Benign

0.021

T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.53

N;.;.;.

PhyloP100

1.4

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.028

D;D;D;D

Sift4G

Benign

0.071

T;T;T;T

Polyphen

0.027

B;.;.;B

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over