NM_016953.4:c.171delT
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2
The NM_016953.4(PDE11A):c.171delT(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
Consequence
NM_016953.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PDE11A | ENST00000286063.11 | c.171delT | p.Thr58ProfsTer41 | frameshift_variant | Exon 1 of 20 | 1 | NM_016953.4 | ENSP00000286063.5 | ||
PDE11A | ENST00000358450.8 | c.162+32035delT | intron_variant | Intron 2 of 20 | 1 | ENSP00000351232.4 |
Frequencies
GnomAD3 genomes AF: 0.00183 AC: 278AN: 152134Hom.: 7 Cov.: 32
GnomAD3 exomes AF: 0.00563 AC: 1403AN: 249420Hom.: 35 AF XY: 0.00778 AC XY: 1050AN XY: 134992
GnomAD4 exome AF: 0.00313 AC: 4575AN: 1461430Hom.: 115 Cov.: 34 AF XY: 0.00441 AC XY: 3207AN XY: 726970
GnomAD4 genome AF: 0.00183 AC: 279AN: 152252Hom.: 7 Cov.: 32 AF XY: 0.00248 AC XY: 185AN XY: 74462
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
PDE11A: BS1, BS2 -
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. -
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Pigmented nodular adrenocortical disease, primary, 2 Uncertain:1Benign:1
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not specified Benign:1
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
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at