rs3821010

chr2-177817928-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_016953.4(PDE11A):c.1577-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 1,396,904 control chromosomes in the GnomAD database, including 75,446 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (14371 hom., cov: 31)
  • Exomes 𝑓: 0.31 (61075 hom.)
• Consequence: PDE11A NM_016953.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004978
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.41

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-177817928-A-G is Benign according to our data. Variant chr2-177817928-A-G is described in ClinVar as [Benign]. Clinvar id is 1327001.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-177817928-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE11A	NM_016953.4	c.1577-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000286063.11
PDE11A	NM_001077196.2	c.245-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
PDE11A	NM_001077197.2	c.827-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
PDE11A	NM_001077358.2	c.503-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE11A	ENST00000286063.11	c.1577-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_016953.4	P1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61646 AN: 151786 Hom.: 14355 Cov.: 31

Gnomad AFR AF: 0.644

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.420

GnomAD3 exomes AF: 0.324 AC: 81066 AN: 250122 Hom.: 14669 AF XY: 0.325 AC XY: 43891 AN XY: 135210

Gnomad AFR exome AF: 0.648

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.314

Gnomad SAS exome AF: 0.338

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.305 AC: 380217 AN: 1245000 Hom.: 61075 Cov.: 20 AF XY: 0.308 AC XY: 194133 AN XY: 630134

Gnomad4 AFR exome AF: 0.640

Gnomad4 AMR exome AF: 0.219

Gnomad4 ASJ exome AF: 0.373

Gnomad4 EAS exome AF: 0.298

Gnomad4 SAS exome AF: 0.335

Gnomad4 FIN exome AF: 0.238

Gnomad4 NFE exome AF: 0.297

Gnomad4 OTH exome AF: 0.328

GnomAD4 genome AF: 0.406 AC: 61704 AN: 151904 Hom.: 14371 Cov.: 31 AF XY: 0.400 AC XY: 29705 AN XY: 74254

Gnomad4 AFR AF: 0.644

Gnomad4 AMR AF: 0.310

Gnomad4 ASJ AF: 0.385

Gnomad4 EAS AF: 0.319

Gnomad4 SAS AF: 0.332

Gnomad4 FIN AF: 0.235

Gnomad4 NFE AF: 0.321

Gnomad4 OTH AF: 0.417

Alfa AF: 0.349 Hom.: 15889

Bravo AF: 0.422

Asia WGS AF: 0.297 AC: 1035 AN: 3478

EpiCase AF: 0.339

EpiControl AF: 0.347

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pigmented nodular adrenocortical disease, primary, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	5.7
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.0020
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: rs3821010; hg19: chr2-178682655; COSMIC: COSV53695596;