19-10449102-T-C

Variant names:

• chr19-10449102-T-C
• rs1471202678
• NM_001111307.2:c.572T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001111307.2(PDE4A):​c.572T>C​(p.Val191Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PDE4A NM_001111307.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87

Genes affected

PDE4A (HGNC:8780): (phosphodiesterase 4A) The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE4 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 described for this gene.[provided by RefSeq, Jul 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE4A	NM_001111307.2	c.572T>C	p.Val191Ala	missense_variant	Exon 4 of 15	ENST00000380702.7	NP_001104777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE4A	ENST00000380702.7	c.572T>C	p.Val191Ala	missense_variant	Exon 4 of 15	1	NM_001111307.2	ENSP00000370078.3
PDE4A	ENST00000592685.5	c.506T>C	p.Val169Ala	missense_variant	Exon 6 of 17	1		ENSP00000468507.1
PDE4A	ENST00000293683.9	c.494T>C	p.Val165Ala	missense_variant	Exon 4 of 15	1		ENSP00000293683.4
PDE4A	ENST00000440014.6	c.389T>C	p.Val130Ala	missense_variant	Exon 4 of 15	1		ENSP00000394754.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461422 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.572T>C (p.V191A) alteration is located in exon 4 (coding exon 4) of the PDE4A gene. This alteration results from a T to C substitution at nucleotide position 572, causing the valine (V) at amino acid position 191 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.6	.;M;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.0	.;.;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Uncertain	0.032	D;D;D;D
Polyphen		0.99, 1.0, 1.0	.;D;D;D
Vest4		0.89
MutPred		0.43		.;Loss of stability (P = 0.0675);.;.;
MVP		0.74
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.38

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1471202678; hg19: chr19-10559778;