rs10075508

Variant names:

• chr5-58973026-C-T
• rs10075508
• NM_001104631.2:c.*1638G>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.*1638G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 151,992 control chromosomes in the GnomAD database, including 2,101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2101 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDE4D NM_001104631.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.786
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-58973026-C-T is Benign according to our data. Variant chr5-58973026-C-T is described in ClinVar as Benign. ClinVar VariationId is 353959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.184 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4D	NM_001104631.2	MANE Select	c.*1638G>A		3_prime_UTR	Exon 15 of 15	NP_001098101.1
	PDE4D	NM_001165899.2		c.*1638G>A		3_prime_UTR	Exon 17 of 17	NP_001159371.1
	PDE4D	NM_001364599.1		c.*1638G>A		3_prime_UTR	Exon 17 of 17	NP_001351528.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE4D	ENST00000340635.11	TSL:1 MANE Select	c.*1638G>A		3_prime_UTR	Exon 15 of 15	ENSP00000345502.6
	PDE4D	ENST00000507116.6	TSL:1	c.*1638G>A		3_prime_UTR	Exon 15 of 15	ENSP00000424852.1
	PDE4D	ENST00000636120.1	TSL:5	c.*1638G>A		3_prime_UTR	Exon 15 of 15	ENSP00000490821.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24470 AN: 151874 Hom.: 2100 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.138

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.161 AC: 24489 AN: 151992 Hom.: 2101 Cov.: 32 AF XY: 0.165 AC XY: 12245 AN XY: 74288

African (AFR) AF: 0.148 AC: 6130 AN: 41516

American (AMR) AF: 0.190 AC: 2901 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0861 AC: 299 AN: 3472

East Asian (EAS) AF: 0.181 AC: 936 AN: 5172

South Asian (SAS) AF: 0.131 AC: 628 AN: 4800

European-Finnish (FIN) AF: 0.216 AC: 2274 AN: 10522

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10871 AN: 67922

Other (OTH) AF: 0.142 AC: 300 AN: 2110

Alfa AF: 0.157 Hom.: 413

Bravo AF: 0.156

Asia WGS AF: 0.167 AC: 578 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Acrodysostosis 2 with or without hormone resistance (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.15
DANN	Benign	0.62
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10075508; hg19: chr5-58268853;