Genetic Variant PDE1C:p.Ala260Ser (chr7-31850714-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BS2_Supporting

The NM_001191057.4(PDE1C):c.778G>T(p.Ala260Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,612,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PDE1C
NM_001191057.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 6.00

Variant links:

Genes affected

PDE1C (HGNC:8776): (phosphodiesterase 1C) This gene encodes an enzyme that belongs to the 3'5'-cyclic nucleotide phosphodiesterase family. Members of this family catalyze hydrolysis of the cyclic nucleotides, cyclic adenosine monophosphate and cyclic guanosine monophosphate, to the corresponding nucleoside 5'-monophosphates. The enzyme encoded by this gene regulates proliferation and migration of vascular smooth muscle cells, and neointimal hyperplasia. This enzyme also plays a role in pathological vascular remodeling by regulating the stability of growth factor receptors, such as PDGF-receptor-beta. [provided by RefSeq, Jul 2016]

PDE1C links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP5

Variant 7-31850714-C-A is Pathogenic according to our data. Variant chr7-31850714-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433528.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE1C	NM_001191057.4 link	c.778G>T	p.Ala260Ser	missense_variant	Exon 8 of 18	ENST00000396191.6	NP_001177986.1	Q14123-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE1C	ENST00000396191.6 link	c.778G>T	p.Ala260Ser	missense_variant	Exon 8 of 18	2	NM_001191057.4	ENSP00000379494.1		Q14123-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000773

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

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251008

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135652

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000654

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1460846

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726736

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000303

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hearing loss, autosomal dominant 74

Pathogenic:1

Oct 12, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Autosomal dominant nonsyndromic hearing loss

Pathogenic:1

Aug 14, 2017

Dr. Liu's Molecular Genetics Laboratory, University of Miami Miller School of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The affected members show autosomal dominant progressive hearing loss. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;D;D;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;.;D;.;D

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.64

D;D;D;D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

2.0

.;M;M;M;M

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.0

D;D;D;D;D

REVEL

Uncertain

0.64

Sift

Uncertain

0.021

D;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D

Polyphen

1.0, 1.0

.;D;D;D;D

Vest4

0.64

MutPred

0.78

.;Gain of glycosylation at A260 (P = 0.0193);Gain of glycosylation at A260 (P = 0.0193);Gain of glycosylation at A260 (P = 0.0193);Gain of glycosylation at A260 (P = 0.0193);

MVP

0.90

MPC

1.3

ClinPred

0.45

GERP RS

5.9

Varity_R

0.49

gMVP

0.79

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over