rs875989839

Positions:

• chr6-165450242-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001385079.1(PDE10A):​c.1144G>C​(p.Ala382Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE10A NM_001385079.1 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.56

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]

PDE10A (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 6-165450242-C-G is Pathogenic according to our data. Variant chr6-165450242-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 225634.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-165450242-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE10A	NM_001385079.1	c.1144G>C	p.Ala382Pro	missense_variant, splice_region_variant	4/22	ENST00000539869.4	NP_001372008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE10A	ENST00000539869.4	c.1144G>C	p.Ala382Pro	missense_variant, splice_region_variant	4/22	1	NM_001385079.1	ENSP00000438284.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Infantile-onset generalized dyskinesia with orofacial involvement Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 29, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	.;T;.;.;.;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.9	.;.;.;.;.;L
PrimateAI	Uncertain	0.78	T
REVEL	Uncertain	0.59
Polyphen		1.0	.;.;.;.;.;D
MutPred		0.71		.;.;.;.;.;Loss of ubiquitination at K104 (P = 0.07);
MVP		0.81
MPC		2.1
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.80
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.010		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: rs875989839; hg19: chr6-165863730;