rs875989841

Positions:

• chr6-165418735-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_001385079.1(PDE10A):​c.1696T>C​(p.Phe566Leu) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE10A NM_001385079.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.74

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 Pathogenic. Variant got 12 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, 0.819
• PP5: Variant 6-165418735-A-G is Pathogenic according to our data. Variant chr6-165418735-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 225636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-165418735-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE10A	NM_001385079.1	c.1696T>C	p.Phe566Leu	missense_variant	11/22	ENST00000539869.4	NP_001372008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE10A	ENST00000539869.4	c.1696T>C	p.Phe566Leu	missense_variant	11/22	1	NM_001385079.1	ENSP00000438284	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Striatal degeneration, autosomal dominant 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 27, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 29, 2016	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 05, 2020

This variant has been observed in individual(s) with autosomal dominant childhood onset chorea with bilateral striatal lesions (PMID: 27058447, 29165877). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 225636). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 300 of the PDE10A protein (p.Phe300Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. Experimental studies have shown that this variant affects PDE10A protein function (PMID: 27058447). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	.;T;.;.;.;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.4	.;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.2	.;.;.;.;D;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.013	.;.;.;.;D;.
Polyphen		0.99	.;.;.;.;.;D
MutPred		0.60		.;.;.;.;.;Loss of sheet (P = 0.0315);
MVP		0.62
MPC		2.0
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.95
gMVP		0.88

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: rs875989841; hg19: chr6-165832223;