15-84982325-C-T

Variant names:

• chr15-84982325-C-T
• rs11540803
• NM_002605.3:c.163C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002605.3(PDE8A):​c.163C>T​(p.Leu55Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000085 in 1,175,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: PDE8A NM_002605.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.109
• Publications: 0 publications found

Genes affected

PDE8A (HGNC:8793): (phosphodiesterase 8A) The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE8 subfamily. This PDE hydrolyzes the second messenger, cAMP, which is a regulator and mediator of a number of cellular responses to extracellular signals. Thus, by regulating the cellular concentration of cAMP, this protein plays a key role in many important physiological processes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04358363).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002605.3. 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
	PDE8A	NM_002605.3	MANE Select	c.163C>T	p.Leu55Phe	missense	Exon 1 of 22	NP_002596.1
	PDE8A	NM_173454.1		c.163C>T	p.Leu55Phe	missense	Exon 1 of 21	NP_775656.1
	PDE8A	NM_001243137.2		c.-31+1640C>T		intron	N/A	NP_001230066.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE8A	ENST00000394553.6	TSL:1 MANE Select	c.163C>T	p.Leu55Phe	missense	Exon 1 of 22	ENSP00000378056.1
	PDE8A	ENST00000310298.8	TSL:1	c.163C>T	p.Leu55Phe	missense	Exon 2 of 23	ENSP00000311453.4
	PDE8A	ENST00000339708.9	TSL:1	c.163C>T	p.Leu55Phe	missense	Exon 1 of 21	ENSP00000340679.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.50e-7 AC: 1 AN: 1175922 Hom.: 0 Cov.: 31 AF XY: 0.00000176 AC XY: 1 AN XY: 568126

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23856

American (AMR) AF: 0.00 AC: 0 AN: 9838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15934

East Asian (EAS) AF: 0.00 AC: 0 AN: 27710

South Asian (SAS) AF: 0.0000222 AC: 1 AN: 45080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 974730

Other (OTH) AF: 0.00 AC: 0 AN: 47750

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.3
DANN	Benign	0.92
DEOGEN2	Benign	0.088	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.11
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.15
Sift	Benign	0.079	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.031
MutPred		0.17		Loss of stability (P = 0.0742)
MVP		0.26
MPC		0.20
ClinPred		0.049	T
GERP RS		-1.3
PromoterAI		-0.022	Neutral
Varity_R		0.043
gMVP		0.069

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: rs11540803; hg19: chr15-85525556;