6-165333102-C-T

Position:

• chr6-165333102-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The ENST00000539869.4(PDE10A):​c.3091G>A​(p.Val1031Met) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE10A ENST00000539869.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

Genes affected

PDE10A (HGNC:8772): (phosphodiesterase 10A) The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase family. It plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This protein can hydrolyze both cAMP and cGMP to the corresponding nucleoside 5' monophosphate, but has higher affinity for cAMP, and is more efficient with cAMP as substrate. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PDE10A. . Gene score misZ 3.758 (greater than the threshold 3.09). Trascript score misZ 4.0307 (greater than threshold 3.09). GenCC has associacion of gene with infantile-onset generalized dyskinesia with orofacial involvement, childhood-onset benign chorea with striatal involvement, dyskinesia, limb and orofacial, infantile-onset, striatal degeneration, autosomal dominant 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30865535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE10A	NM_001385079.1	c.3091G>A	p.Val1031Met	missense_variant	22/22	ENST00000539869.4	NP_001372008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE10A	ENST00000539869.4	c.3091G>A	p.Val1031Met	missense_variant	22/22	1	NM_001385079.1	ENSP00000438284	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 765 of the PDE10A protein (p.Val765Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PDE10A-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PDE10A protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0032	.;T;.;.;.;T
Eigen	Benign	0.062
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.31	T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.90	.;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
REVEL	Uncertain	0.33
Polyphen		0.0060	.;.;.;.;.;B
MutPred		0.62		.;.;.;.;.;Gain of catalytic residue at V755 (P = 6e-04);
MVP		0.46
MPC		0.82
ClinPred		0.68	D
GERP RS		5.0
Varity_R		0.33
gMVP		0.19

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: chr6-165746591;