rs778899140

Positions:

• chr6-165450268-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_001385079.1(PDE10A):​c.1118A>G​(p.Tyr373Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PDE10A NM_001385079.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.67

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PDE10A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8
• PP5: Variant 6-165450268-T-C is Pathogenic according to our data. Variant chr6-165450268-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225633.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-165450268-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE10A	NM_001385079.1	c.1118A>G	p.Tyr373Cys	missense_variant	4/22	ENST00000539869.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE10A	ENST00000539869.4	c.1118A>G	p.Tyr373Cys	missense_variant	4/22	1	NM_001385079.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249442 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454546 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 723442

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

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

- -

Global developmental delay;C1858120:Generalized hypotonia Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
REVEL	Uncertain	0.63
Polyphen		1.0	.;.;.;.;.;D
MutPred		0.51		.;.;.;.;.;Gain of catalytic residue at S101 (P = 0.0643);
MVP		0.63
MPC		2.1
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.53
gMVP		0.77

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: rs778899140; hg19: chr6-165863756;