NM_018906.3:c.866T>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_018906.3(PCDHA3):c.866T>C(p.Ile289Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,614,098 control chromosomes in the GnomAD database, including 12,557 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.11 ( 1015 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11542 hom. )

Consequence

PCDHA3
NM_018906.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0950

Variant links:

Genes affected

PCDHA3 (HGNC:8669): (protocadherin alpha 3) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA3 links:

PCDHA1 (HGNC:8663): (protocadherin alpha 1) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA1 links:

PCDHA2 (HGNC:8668): (protocadherin alpha 2) This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

PCDHA2 links:

ENSG00000279726 (HGNC:):

ENSG00000279726 links:

PCDHA@ (HGNC:8662):

PCDHA@ links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012852252).

BP6

Variant 5-140802063-T-C is Benign according to our data. Variant chr5-140802063-T-C is described in ClinVar as [Benign]. Clinvar id is 3060497.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHA3	NM_018906.3 link	c.866T>C	p.Ile289Thr	missense_variant	Exon 1 of 4	ENST00000522353.3	NP_061729.1	Q9Y5H8-1
PCDHA1	NM_018900.4 link	c.2394+13379T>C		intron_variant	Intron 1 of 3	ENST00000504120.4	NP_061723.1	Q9Y5I3-1
PCDHA2	NM_018905.3 link	c.2388+4711T>C		intron_variant	Intron 1 of 3	ENST00000526136.2	NP_061728.1	Q9Y5H9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCDHA3	ENST00000522353.3 link	c.866T>C	p.Ile289Thr	missense_variant	Exon 1 of 4	1	NM_018906.3	ENSP00000429808.2	Q9Y5H8-1
PCDHA1	ENST00000504120.4 link	c.2394+13379T>C		intron_variant	Intron 1 of 3	1	NM_018900.4	ENSP00000420840.3	Q9Y5I3-1
PCDHA2	ENST00000526136.2 link	c.2388+4711T>C		intron_variant	Intron 1 of 3	1	NM_018905.3	ENSP00000431748.1	Q9Y5H9-1

Frequencies

GnomAD3 genomes

AF:

0.108

AC:

16370

AN:

152130

Hom.:

1015

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0686

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.0843

Gnomad ASJ

AF:

0.163

Gnomad EAS

AF:

0.0709

Gnomad SAS

AF:

0.0924

Gnomad FIN

AF:

0.188

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.126

Gnomad OTH

AF:

0.0999

GnomAD3 exomes

AF:

0.107

AC:

26793

AN:

251414

Hom.:

1722

AF XY:

0.107

AC XY:

14521

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0684

Gnomad AMR exome

AF:

0.0510

Gnomad ASJ exome

AF:

0.153

Gnomad EAS exome

AF:

0.0733

Gnomad SAS exome

AF:

0.0813

Gnomad FIN exome

AF:

0.190

Gnomad NFE exome

AF:

0.121

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.121

AC:

177385

AN:

1461850

Hom.:

11542

Cov.:

AF XY:

0.120

AC XY:

87424

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0681

Gnomad4 AMR exome

AF:

0.0545

Gnomad4 ASJ exome

AF:

0.160

Gnomad4 EAS exome

AF:

0.0594

Gnomad4 SAS exome

AF:

0.0823

Gnomad4 FIN exome

AF:

0.188

Gnomad4 NFE exome

AF:

0.127

Gnomad4 OTH exome

AF:

0.118

GnomAD4 genome

AF:

0.107

AC:

16361

AN:

152248

Hom.:

1015

Cov.:

AF XY:

0.110

AC XY:

8168

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0683

Gnomad4 AMR

AF:

0.0840

Gnomad4 ASJ

AF:

0.163

Gnomad4 EAS

AF:

0.0710

Gnomad4 SAS

AF:

0.0925

Gnomad4 FIN

AF:

0.188

Gnomad4 NFE

AF:

0.126

Gnomad4 OTH

AF:

0.0989

Alfa

AF:

0.118

Hom.:

2023

Bravo

AF:

0.0962

TwinsUK

AF:

0.131

AC:

484

ALSPAC

AF:

0.126

AC:

486

ESP6500AA

AF:

0.0719

AC:

317

ESP6500EA

AF:

0.121

AC:

1039

ExAC

AF:

0.105

AC:

12761

Asia WGS

AF:

0.0820

AC:

286

AN:

3478

EpiCase

AF:

0.114

EpiControl

AF:

0.112

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PCDHA3-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.026

.;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.31

T;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.80

N;N

PROVEAN

Uncertain

-2.6

D;N

REVEL

Benign

0.067

Sift

Benign

0.14

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.0060

B;B

Vest4

0.024

ClinPred

0.0027

GERP RS

2.5

Varity_R

0.13

gMVP

0.068

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