3-57556966-G-T

Position:

• chr3-57556966-G-T

Variant summary

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

The NM_177966.7(PDE12):​c.587G>T​(p.Arg196Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE12 NM_177966.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

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=0.17995134).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE12	NM_177966.7	c.587G>T	p.Arg196Leu	missense_variant	1/3	ENST00000311180.9	NP_808881.3
PDE12	NM_001322176.2	c.587G>T	p.Arg196Leu	missense_variant	1/3		NP_001309105.1
PDE12	NM_001322177.2	c.587G>T	p.Arg196Leu	missense_variant	1/2		NP_001309106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE12	ENST00000311180.9	c.587G>T	p.Arg196Leu	missense_variant	1/3	1	NM_177966.7	ENSP00000309142.7
PDE12	ENST00000487257.1	c.587G>T	p.Arg196Leu	missense_variant	1/2	1		ENSP00000420626.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Aug 01, 2024

The c.587G>T (p.R196L) alteration is located in exon 1 (coding exon 1) of the PDE12 gene. This alteration results from a G to T substitution at nucleotide position 587, causing the arginine (R) at amino acid position 196 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	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.048
Sift	Benign	0.17	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0010	B;B
Vest4		0.37
MutPred		0.44		Gain of glycosylation at Y198 (P = 0.0185);Gain of glycosylation at Y198 (P = 0.0185);
MVP		0.31
ClinPred		0.12	T
GERP RS		3.2
Varity_R		0.16
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-57542693;