6-165339323-A-C
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting
The NM_001385079.1(PDE10A):āc.2931T>Gā(p.Ile977Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,606,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00034 ( 0 hom., cov: 33)
Exomes š: 0.00034 ( 0 hom. )
Consequence
PDE10A
NM_001385079.1 missense
NM_001385079.1 missense
Scores
7
9
Clinical Significance
Conservation
PhyloP100: -0.338
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
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=0.17015985).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000335 (51/152180) while in subpopulation NFE AF= 0.000647 (44/68022). AF 95% confidence interval is 0.000495. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PDE10A | NM_001385079.1 | c.2931T>G | p.Ile977Met | missense_variant | 20/22 | ENST00000539869.4 | NP_001372008.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PDE10A | ENST00000539869.4 | c.2931T>G | p.Ile977Met | missense_variant | 20/22 | 1 | NM_001385079.1 | ENSP00000438284 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000335 AC: 51AN: 152180Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000271 AC: 68AN: 251208Hom.: 0 AF XY: 0.000280 AC XY: 38AN XY: 135800
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GnomAD4 exome AF: 0.000343 AC: 498AN: 1453956Hom.: 0 Cov.: 27 AF XY: 0.000349 AC XY: 253AN XY: 723936
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GnomAD4 genome AF: 0.000335 AC: 51AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23AN XY: 74344
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 12, 2021 | The c.2133T>G (p.I711M) alteration is located in exon 20 (coding exon 20) of the PDE10A gene. This alteration results from a T to G substitution at nucleotide position 2133, causing the isoleucine (I) at amino acid position 711 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 18, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 711 of the PDE10A protein (p.Ile711Met). This variant is present in population databases (rs148138380, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with PDE10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 2059987). 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
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;.;.;.;.;L
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
REVEL
Uncertain
Polyphen
0.060
.;.;.;.;.;B
MVP
MPC
1.7
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at