rs16889108

Variant names:

• chr5-59039095-G-T
• rs16889108
• ENST00000358923.10:c.-136C>A

Variant summary

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

The NM_001197222.2(PDE4D):​c.13C>A​(p.Pro5Thr) variant causes a missense 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. 5/5 in silico tools predict 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 NM_001197222.2 missense
• 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

PDE4D-AS1 (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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001197222.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4D	NM_001104631.2	MANE Select	c.809-124C>A		intron	N/A	NP_001098101.1	A0A140VJR0
	PDE4D	NM_001197222.2		c.13C>A	p.Pro5Thr	missense	Exon 1 of 10	NP_001184151.1
	PDE4D	NM_001197221.2		c.-136C>A		5_prime_UTR	Exon 1 of 11	NP_001184150.1	Q08499-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4D	ENST00000358923.10	TSL:1	c.-136C>A		5_prime_UTR	Exon 1 of 11	ENSP00000351800.6	Q08499-5
	PDE4D	ENST00000340635.11	TSL:1 MANE Select	c.809-124C>A		intron	N/A	ENSP00000345502.6	Q08499-1
	PDE4D	ENST00000502484.6	TSL:1	c.626-124C>A		intron	N/A	ENSP00000423094.2	Q08499-11

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	PDE4D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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;