rs529789124

Positions:

chr2-178072266-TA-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2

The NM_016953.4(PDE11A):c.171del(p.Thr58ProfsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,613,682 control chromosomes in the GnomAD database, including 122 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0018 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 115 hom. )

Consequence

PDE11A
NM_016953.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 0.635

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 2-178072266-TA-T is Benign according to our data. Variant chr2-178072266-TA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208602.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr2-178072266-TA-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00183 (279/152252) while in subpopulation SAS AF= 0.041 (197/4808). AF 95% confidence interval is 0.0363. There are 7 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 279 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE11A	NM_016953.4 linkuse as main transcript	c.171del	p.Thr58ProfsTer41	frameshift_variant	1/20	ENST00000286063.11	NP_058649.3
PDE11A	NM_001077197.2 linkuse as main transcript	c.162+32035del		intron_variant			NP_001070665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE11A	ENST00000286063.11 linkuse as main transcript	c.171del	p.Thr58ProfsTer41	frameshift_variant	1/20	1	NM_016953.4	ENSP00000286063	P1	Q9HCR9-1
PDE11A	ENST00000358450.8 linkuse as main transcript	c.162+32035del		intron_variant		1		ENSP00000351232		Q9HCR9-2

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

278

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0407

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00563

AC:

1403

AN:

249420

Hom.:

AF XY:

0.00778

AC XY:

1050

AN XY:

134992

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00885

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.0382

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000924

Gnomad OTH exome

AF:

0.00460

GnomAD4 exome

AF:

0.00313

AC:

4575

AN:

1461430

Hom.:

115

Cov.:

AF XY:

0.00441

AC XY:

3207

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.00926

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0394

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000498

Gnomad4 OTH exome

AF:

0.00406

GnomAD4 genome

AF:

0.00183

AC:

279

AN:

152252

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

185

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0410

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000471

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00317

Hom.:

Bravo

AF:

0.000937

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	PDE11A: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 28, 2016	The p.Thr58ProfsX41 variant in PDE11A has been reported in 1 individual with adrenocortical hyperplasia and Cushing syndrome, and segregated with disease in 1 parent with hypertension, obesity, and bilaterally enlarged adrenal glands (Horvath 2006). This variant has also been reported in 1 individual with acromegaly (Peverelli 2009) and in 3 individuals with Carney complex who also carried PRKAR1A variants, and was considered to be a possible modifier of disease in these individuals (Libe 2011). The p.Thr58ProfsX41 variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 58 and leads to a premature termination codon 41 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Several loss-of-function PDE11A variants have been described in individuals with Cushing syndrome and with adrenal hyperplasia with established loss-of-heterozygosity in somatic tissue (Horvath 2006, Carney 2010, Libe 2011). However, this variant has been identified in 4% (647/16342; 17 homozygotes) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org) calling into question the validity of a pathogenic interpretation and leaving the clinical significance of the p.Thr58ProfsX41 variant as uncertain. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Pigmented nodular adrenocortical disease, primary, 2

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 12, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PDE11A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Bardet-Biedl syndrome 16

Benign:1

Likely benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The c.171delT variant in PDE11A has been identified in 6 individuals with possible adrenocortical hyperplasia (PMID: 16767104, 19671705, 20351491, 21047926), and has been identified in >3% of South Asian chromosomes and 18 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for adrenocortical hyperplasia. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over