5-59291199-A-G

Variant names:

• chr5-59291199-A-G
• rs27178
• NM_001104631.2:c.456-75231T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001104631.2(PDE4D):​c.456-75231T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 151,918 control chromosomes in the GnomAD database, including 25,168 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (25168 hom., cov: 32)
• Consequence: PDE4D NM_001104631.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.05).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001104631.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4D	NM_001104631.2	MANE Select	c.456-75231T>C		intron	N/A	NP_001098101.1
	PDE4D	NM_001165899.2		c.273-75231T>C		intron	N/A	NP_001159371.1
	PDE4D	NM_001364599.1		c.273-75231T>C		intron	N/A	NP_001351528.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4D	ENST00000340635.11	TSL:1 MANE Select	c.456-75231T>C		intron	N/A	ENSP00000345502.6
	PDE4D	ENST00000502484.6	TSL:1	c.273-75231T>C		intron	N/A	ENSP00000423094.2
	PDE4D	ENST00000507116.6	TSL:1	c.264-75231T>C		intron	N/A	ENSP00000424852.1

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85292 AN: 151800 Hom.: 25135 Cov.: 32

Gnomad AFR AF: 0.721

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.743

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.530

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.562 AC: 85375 AN: 151918 Hom.: 25168 Cov.: 32 AF XY: 0.564 AC XY: 41845 AN XY: 74222

African (AFR) AF: 0.721 AC: 29932 AN: 41496

American (AMR) AF: 0.624 AC: 9511 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 1761 AN: 3468

East Asian (EAS) AF: 0.742 AC: 3821 AN: 5150

South Asian (SAS) AF: 0.487 AC: 2347 AN: 4820

European-Finnish (FIN) AF: 0.460 AC: 4849 AN: 10544

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.463 AC: 31440 AN: 67878

Other (OTH) AF: 0.536 AC: 1130 AN: 2110

Alfa AF: 0.506 Hom.: 2450

Bravo AF: 0.580

Asia WGS AF: 0.639 AC: 2219 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.81
DANN	Benign	0.38
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs27178; hg19: chr5-58587025;