NM_001104631.2:c.1287+6G>A

Variant names:

• chr5-58990798-C-T
• rs1553114
• NM_001104631.2:c.1287+6G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001104631.2(PDE4D):​c.1287+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 1,467,162 control chromosomes in the GnomAD database, including 515,920 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (50820 hom., cov: 30)
  • Exomes 𝑓: 0.84 (465100 hom.)
• Consequence: PDE4D NM_001104631.2 splice_region, intron
• Scores: Splicing: ADA: 0.00009314
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0420
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 5-58990798-C-T is Benign according to our data. Variant chr5-58990798-C-T is described in ClinVar as Benign. ClinVar VariationId is 353992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE4D	NM_001104631.2	c.1287+6G>A		splice_region_variant, intron_variant	Intron 9 of 14	ENST00000340635.11	NP_001098101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE4D	ENST00000340635.11	c.1287+6G>A		splice_region_variant, intron_variant	Intron 9 of 14	1	NM_001104631.2	ENSP00000345502.6

Frequencies

GnomAD3 genomes AF: 0.817 AC: 124007 AN: 151818 Hom.: 50790 Cov.: 30

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.871

Gnomad AMR AF: 0.881

Gnomad ASJ AF: 0.808

Gnomad EAS AF: 0.844

Gnomad SAS AF: 0.804

Gnomad FIN AF: 0.828

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.842

Gnomad OTH AF: 0.816

GnomAD2 exomes AF: 0.838 AC: 173259 AN: 206700 AF XY: 0.835

Gnomad AFR exome AF: 0.734

Gnomad AMR exome AF: 0.919

Gnomad ASJ exome AF: 0.821

Gnomad EAS exome AF: 0.853

Gnomad FIN exome AF: 0.829

Gnomad NFE exome AF: 0.837

Gnomad OTH exome AF: 0.841

GnomAD4 exome AF: 0.840 AC: 1104911 AN: 1315228 Hom.: 465100 Cov.: 19 AF XY: 0.838 AC XY: 551544 AN XY: 658034

African (AFR) AF: 0.734 AC: 22540 AN: 30694

American (AMR) AF: 0.914 AC: 37250 AN: 40742

Ashkenazi Jewish (ASJ) AF: 0.819 AC: 20415 AN: 24914

East Asian (EAS) AF: 0.843 AC: 32189 AN: 38192

South Asian (SAS) AF: 0.800 AC: 63025 AN: 78784

European-Finnish (FIN) AF: 0.831 AC: 42809 AN: 51512

Middle Eastern (MID) AF: 0.784 AC: 4329 AN: 5520

European-Non Finnish (NFE) AF: 0.845 AC: 835889 AN: 989512

Other (OTH) AF: 0.839 AC: 46465 AN: 55358

GnomAD4 genome AF: 0.817 AC: 124084 AN: 151934 Hom.: 50820 Cov.: 30 AF XY: 0.818 AC XY: 60723 AN XY: 74242

African (AFR) AF: 0.746 AC: 30869 AN: 41406

American (AMR) AF: 0.881 AC: 13446 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 2803 AN: 3470

East Asian (EAS) AF: 0.844 AC: 4355 AN: 5158

South Asian (SAS) AF: 0.805 AC: 3876 AN: 4812

European-Finnish (FIN) AF: 0.828 AC: 8714 AN: 10530

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.842 AC: 57259 AN: 67978

Other (OTH) AF: 0.819 AC: 1729 AN: 2112

Alfa AF: 0.834 Hom.: 199622

Bravo AF: 0.819

Asia WGS AF: 0.835 AC: 2904 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Acrodysostosis 2 with or without hormone resistance Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.4
DANN	Benign	0.48
PhyloP100		0.042
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000093
dbscSNV1_RF	Benign	0.0
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: rs1553114; hg19: chr5-58286625;