rs16889108

Variant names:

• chr5-59039095-G-T
• rs16889108
• ENST00000515011.5:n.421C>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000515011.5(PDE4D):​n.421C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,453,192 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (90 hom.)
• Consequence: PDE4D ENST00000515011.5 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.47
• Publications: 6 publications found

Genes affected

PDE4D (HGNC:8783): (phosphodiesterase 4D) This gene encodes one of four mammalian counterparts to the fruit fly 'dunce' gene. The encoded protein has 3',5'-cyclic-AMP phosphodiesterase activity and degrades cAMP, which acts as a signal transduction molecule in multiple cell types. This gene uses different promoters to generate multiple alternatively spliced transcript variants that encode functional proteins.[provided by RefSeq, Sep 2009]

PDE4D Gene-Disease associations (from GenCC):

• acrodysostosis 2 with or without hormone resistance

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• acrodysostosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acrodysostosis with multiple hormone resistance

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• chromosome 5q12 deletion syndrome

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000247345 (HGNC:58182):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 5-59039095-G-T is Benign according to our data. Variant chr5-59039095-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1293 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE4D	NM_001104631.2	c.809-124C>A		intron_variant	Intron 5 of 14	ENST00000340635.11	NP_001098101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE4D	ENST00000340635.11	c.809-124C>A		intron_variant	Intron 5 of 14	1	NM_001104631.2	ENSP00000345502.6

Frequencies

GnomAD3 genomes AF: 0.00850 AC: 1293 AN: 152196 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00970 AC: 650 AN: 67008 AF XY: 0.0104

Gnomad AFR exome AF: 0.00301

Gnomad AMR exome AF: 0.00551

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0212

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.00843

GnomAD4 exome AF: 0.0105 AC: 13700 AN: 1300878 Hom.: 90 Cov.: 30 AF XY: 0.0107 AC XY: 6787 AN XY: 634404

African (AFR) AF: 0.00126 AC: 35 AN: 27832

American (AMR) AF: 0.00458 AC: 113 AN: 24654

Ashkenazi Jewish (ASJ) AF: 0.00333 AC: 66 AN: 19802

East Asian (EAS) AF: 0.00 AC: 0 AN: 31306

South Asian (SAS) AF: 0.00236 AC: 154 AN: 65196

European-Finnish (FIN) AF: 0.0180 AC: 718 AN: 39794

Middle Eastern (MID) AF: 0.000383 AC: 2 AN: 5222

European-Non Finnish (NFE) AF: 0.0119 AC: 12251 AN: 1033168

Other (OTH) AF: 0.00670 AC: 361 AN: 53904

GnomAD4 genome AF: 0.00849 AC: 1293 AN: 152314 Hom.: 8 Cov.: 32 AF XY: 0.00863 AC XY: 643 AN XY: 74474

African (AFR) AF: 0.00176 AC: 73 AN: 41584

American (AMR) AF: 0.00418 AC: 64 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00310 AC: 15 AN: 4834

European-Finnish (FIN) AF: 0.0189 AC: 201 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0135 AC: 918 AN: 68026

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.0104 Hom.: 15

Bravo AF: 0.00661

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 28, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PDE4D: BS1, BS2

PDE4D-related disorder Benign:1

Jun 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.75
PhyloP100		2.5
PromoterAI		0.017	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16889108; hg19: chr5-58334922;