rs529789124

chr2-178072266-TA-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.635

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]

ACMG classification

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: {Benign=4, Likely_benign=2, 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 GnomAd at 278 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE11A	NM_016953.4	c.171del	p.Thr58ProfsTer41	frameshift_variant	1/20	ENST00000286063.11
PDE11A	NM_001077197.2	c.162+32035del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE11A	ENST00000286063.11	c.171del	p.Thr58ProfsTer41	frameshift_variant	1/20	1	NM_016953.4	P1
PDE11A	ENST00000358450.8	c.162+32035del		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 278 AN: 152134 Hom.: 7 Cov.: 32

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.: 35 AF XY: 0.00778 AC XY: 1050 AN XY: 134992

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.: 34 AF XY: 0.00441 AC XY: 3207 AN XY: 726970

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.: 7 Cov.: 32 AF XY: 0.00248 AC XY: 185 AN XY: 74462

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.: 4

Bravo AF: 0.000937

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

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	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	PDE11A: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Pigmented nodular adrenocortical disease, primary, 2 Uncertain:1 Benign: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, criteria provided, single submitter

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

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

Other links and lift over

dbSNP: rs529789124; hg19: chr2-178936993; COSMIC: COSV53685455;