3-57556506-G-C

Position:

• chr3-57556506-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177966.7(PDE12):​c.127G>C​(p.Val43Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PDE12 NM_177966.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.71

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16840279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE12	NM_177966.7	c.127G>C	p.Val43Leu	missense_variant	1/3	ENST00000311180.9	NP_808881.3
PDE12	NM_001322176.2	c.127G>C	p.Val43Leu	missense_variant	1/3		NP_001309105.1
PDE12	NM_001322177.2	c.127G>C	p.Val43Leu	missense_variant	1/2		NP_001309106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE12	ENST00000311180.9	c.127G>C	p.Val43Leu	missense_variant	1/3	1	NM_177966.7	ENSP00000309142.7
PDE12	ENST00000487257.1	c.127G>C	p.Val43Leu	missense_variant	1/2	1		ENSP00000420626.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461042 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

The c.127G>C (p.V43L) alteration is located in exon 1 (coding exon 1) of the PDE12 gene. This alteration results from a G to C substitution at nucleotide position 127, causing the valine (V) at amino acid position 43 to be replaced by a leucine (L). 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	Uncertain	0.48
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	0.076
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.062
Sift	Benign	0.18	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.24	B;B
Vest4		0.091
MutPred		0.24		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP		0.45
ClinPred		0.80	D
GERP RS		6.0
Varity_R		0.32
gMVP		0.42

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

Other links and lift over

dbSNP: rs1020036109; hg19: chr3-57542233;