15-84982185-A-T

Variant names:

• chr15-84982185-A-T
• rs1468378020
• NM_002605.3:c.23A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002605.3(PDE8A):​c.23A>T​(p.His8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,331,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H8R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: PDE8A NM_002605.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0720
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.142037).

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.23A>T	p.His8Leu	missense	Exon 1 of 22	NP_002596.1	O60658-1
	PDE8A	NM_173454.1		c.23A>T	p.His8Leu	missense	Exon 1 of 21	NP_775656.1	O60658-2
	PDE8A	NM_001243137.2		c.-31+1500A>T		intron	N/A	NP_001230066.1	O60658-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE8A	ENST00000394553.6	TSL:1 MANE Select	c.23A>T	p.His8Leu	missense	Exon 1 of 22	ENSP00000378056.1	O60658-1
	PDE8A	ENST00000310298.8	TSL:1	c.23A>T	p.His8Leu	missense	Exon 2 of 23	ENSP00000311453.4	O60658-1
	PDE8A	ENST00000339708.9	TSL:1	c.23A>T	p.His8Leu	missense	Exon 1 of 21	ENSP00000340679.5	O60658-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1331694 Hom.: 0 Cov.: 30 AF XY: 0.00000151 AC XY: 1 AN XY: 660156

African (AFR) AF: 0.00 AC: 0 AN: 26796

American (AMR) AF: 0.00 AC: 0 AN: 28112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22802

East Asian (EAS) AF: 0.00 AC: 0 AN: 29122

South Asian (SAS) AF: 0.00 AC: 0 AN: 73776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4066

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1058836

Other (OTH) AF: 0.00 AC: 0 AN: 54546

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.072
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.11
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.012	D
Polyphen		0.023	B
Vest4		0.31
MutPred		0.33		Gain of sheet (P = 0.1208)
MVP		0.38
MPC		0.25
ClinPred		0.53	D
GERP RS		0.58
PromoterAI		-0.0029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.72
Mutation Taster		=63/37	polymorphism

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: rs1468378020; hg19: chr15-85525416;