NM_001104631.2:c.456-178457G>A

Variant names:

• chr5-59394425-C-T
• rs525099
• NM_001104631.2:c.456-178457G>A

Variant summary

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

The NM_001104631.2(PDE4D):​c.456-178457G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 151,938 control chromosomes in the GnomAD database, including 34,823 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 0.67 (34823 hom., cov: 31)
• Consequence: PDE4D NM_001104631.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.703
• Publications: 8 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=-0.61).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.793 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.456-178457G>A		intron	N/A	NP_001098101.1
	PDE4D	NM_001165899.2		c.273-178457G>A		intron	N/A	NP_001159371.1
	PDE4D	NM_001364599.1		c.273-178457G>A		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.456-178457G>A		intron	N/A	ENSP00000345502.6
	PDE4D	ENST00000502484.6	TSL:1	c.273-178457G>A		intron	N/A	ENSP00000423094.2
	PDE4D	ENST00000507116.6	TSL:1	c.264-178457G>A		intron	N/A	ENSP00000424852.1

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101580 AN: 151822 Hom.: 34800 Cov.: 31

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.623

Gnomad EAS AF: 0.717

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.679

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

GnomAD4 genome AF: 0.669 AC: 101655 AN: 151938 Hom.: 34823 Cov.: 31 AF XY: 0.666 AC XY: 49424 AN XY: 74252

African (AFR) AF: 0.800 AC: 33186 AN: 41458

American (AMR) AF: 0.564 AC: 8599 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 2157 AN: 3462

East Asian (EAS) AF: 0.718 AC: 3709 AN: 5168

South Asian (SAS) AF: 0.766 AC: 3682 AN: 4804

European-Finnish (FIN) AF: 0.568 AC: 5974 AN: 10514

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42090 AN: 67960

Other (OTH) AF: 0.672 AC: 1418 AN: 2110

Alfa AF: 0.638 Hom.: 90530

Bravo AF: 0.673

Asia WGS AF: 0.682 AC: 2373 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.5
DANN	Benign	0.40
PhyloP100		0.70
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: rs525099; hg19: chr5-58690251;