6-165333065-G-T

Position:

• chr6-165333065-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001385079.1(PDE10A):​c.3128C>A​(p.Ser1043Tyr) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE10A NM_001385079.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.990

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 1 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=0.11588815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE10A	NM_001385079.1	c.3128C>A	p.Ser1043Tyr	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.3128C>A	p.Ser1043Tyr	missense_variant	22/22	1	NM_001385079.1	ENSP00000438284	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Infantile-onset generalized dyskinesia with orofacial involvement Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Oct 30, 2020

The c.2300C>A; (p.Ser767Tyr) missense variant in exon 23 of 23 of PDE10A has not been reported in affected individuals in the available literature. This variant is absent in gnomADv3 indicating it is not a common benign variant in the populations represented in this database. In silico predictors suggest this variant is Benign (REVEL; score: 0.082) and Damaging (SIFT; score: 0.015). Given the evidence regarding its pathogenicity, the c.2300C>A; (p.Ser767Tyr) variant identified in the PDE10A gene is reported as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.021	.;T;.;.;.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.84	T;T;T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	.;.;.;.;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.64	N;.;.;.;.;.
REVEL	Benign	0.082
Sift	Uncertain	0.015	D;.;.;.;.;.
Polyphen		0.0080	.;.;.;.;.;B
MutPred		0.41		.;.;.;.;.;Loss of disorder (P = 8e-04);
MVP		0.36
MPC		1.2
ClinPred		0.098	T
GERP RS		1.6
Varity_R		0.15
gMVP		0.17

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: chr6-165746554; COSMIC: COSV63103398;