chr6-165339323-A-C

Position:

chr6-165339323-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting

The NM_001385079.1(PDE10A):c.2931T>G(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 (★★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

PDE10A
NM_001385079.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.338

Variant links:

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 links:

Genome browser will be placed here

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 linkuse as main transcript	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 linkuse as main transcript	c.2931T>G	p.Ile977Met	missense_variant	20/22	1	NM_001385079.1	ENSP00000438284	P3

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000271

AC:

AN:

251208

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000932

Gnomad NFE exome

AF:

0.000510

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000343

AC:

498

AN:

1453956

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

253

AN XY:

723936

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000151

Gnomad4 NFE exome

AF:

0.000410

Gnomad4 OTH exome

AF:

0.000366

GnomAD4 genome

AF:

0.000335

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000888

Hom.:

Bravo

AF:

0.000325

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000354

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000830

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

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.031

.;T;.;.;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Benign

0.068

MetaRNN

Benign

0.17

T;T;T;T;T;T

MetaSVM

Uncertain

0.064

MutationAssessor

Benign

1.7

.;.;.;.;.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.75

REVEL

Uncertain

0.51

Polyphen

0.060

.;.;.;.;.;B

MVP

0.60

MPC

1.7

ClinPred

0.15

GERP RS

-10

Varity_R

0.80

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over