Genetic Variant PDE12:p.Ser433Pro (chr3-57557676-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_177966.7(PDE12):c.1297T>C(p.Ser433Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S433T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PDE12
NM_177966.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.59

Publications

0 publications found

Variant links:

Genes affected

PDE12 (HGNC:25386): (phosphodiesterase 12) Enables 3'-5'-exoribonuclease activity. Involved in several processes, including RNA metabolic process; cellular response to cytokine stimulus; and regulation of mitochondrial mRNA stability. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

PDE12 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

PDE12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE12	NM_177966.7 link	c.1297T>C	p.Ser433Pro	missense_variant	Exon 1 of 3	ENST00000311180.9	NP_808881.3	Q6L8Q7-1
PDE12	NM_001322176.2 link	c.1297T>C	p.Ser433Pro	missense_variant	Exon 1 of 3		NP_001309105.1
PDE12	NM_001322177.2 link	c.1297T>C	p.Ser433Pro	missense_variant	Exon 1 of 2		NP_001309106.1	F6T1Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PDE12	ENST00000311180.9 link	c.1297T>C	p.Ser433Pro	missense_variant	Exon 1 of 3	1	NM_177966.7	ENSP00000309142.7	Q6L8Q7-1
PDE12	ENST00000487257.1 link	c.1297T>C	p.Ser433Pro	missense_variant	Exon 1 of 2	1		ENSP00000420626.1	F6T1Q0
PDE12	ENST00000715954.1 link	c.1297T>C	p.Ser433Pro	missense_variant	Exon 1 of 3			ENSP00000520545.1
PDE12	ENST00000715955.1 link	c.1297T>C	p.Ser433Pro	missense_variant	Exon 1 of 4			ENSP00000520546.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461286

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726902

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.0000224

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111706

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

D;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.4

.;M

PhyloP100

4.6

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.1

D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.022

D;D

Polyphen

1.0

D;D

Vest4

0.68

MutPred

0.63

Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);

MVP

0.93

ClinPred

0.98

GERP RS

5.6

Varity_R

0.95

gMVP

0.69

Mutation Taster

=36/64

disease causing

(source)

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

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3-57557676-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over