15-85064410-A-G

Variant names:

• chr15-85064410-A-G
• rs781363493
• NM_002605.3:c.227A>G

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.227A>G​(p.His76Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,607,414 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: PDE8A NM_002605.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77
• Publications: 1 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=0.084581375).

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.227A>G	p.His76Arg	missense	Exon 2 of 22	NP_002596.1	O60658-1
	PDE8A	NM_173454.1		c.227A>G	p.His76Arg	missense	Exon 2 of 21	NP_775656.1	O60658-2
	PDE8A	NM_001243137.2		c.11A>G	p.His4Arg	missense	Exon 2 of 22	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.227A>G	p.His76Arg	missense	Exon 2 of 22	ENSP00000378056.1	O60658-1
	PDE8A	ENST00000310298.8	TSL:1	c.227A>G	p.His76Arg	missense	Exon 3 of 23	ENSP00000311453.4	O60658-1
	PDE8A	ENST00000339708.9	TSL:1	c.227A>G	p.His76Arg	missense	Exon 2 of 21	ENSP00000340679.5	O60658-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250890 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1455220 Hom.: 0 Cov.: 27 AF XY: 0.00000828 AC XY: 6 AN XY: 724428

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 86034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106146

Other (OTH) AF: 0.000150 AC: 9 AN: 60168

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.0082
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.080
Sift	Benign	0.37	T
Sift4G	Benign	0.35	T
Polyphen		0.0070	B
Vest4		0.13
MutPred		0.33		Gain of catalytic residue at H76 (P = 0.1059)
MVP		0.15
MPC		0.24
ClinPred		0.19	T
GERP RS		4.5
Varity_R		0.095
gMVP		0.21
Mutation Taster		=89/11	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: rs781363493; hg19: chr15-85607641;