chr5-140802063-T-C

Variant names:

• chr5-140802063-T-C
• rs3733709
• NM_018906.3:c.866T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.11 (1015 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11542 hom.)
• Consequence: PCDHA3 NM_018906.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0950
• Publications: 16 publications found

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]

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]

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]

ENSG00000279726 (HGNC:):

PCDHA@ (HGNC:8662):

ACMG classification

Our verdict: Benign. The variant received -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 CliVar as Benign. Clinvar id is 3060497.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-140802063-T-C is described in CliVar as Benign. Clinvar id is 3060497.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-140802063-T-C is described in CliVar as Benign. Clinvar id is 3060497.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-140802063-T-C is described in CliVar as Benign. Clinvar id is 3060497.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-140802063-T-C is described in CliVar as Benign. Clinvar id is 3060497.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-140802063-T-C is described in CliVar as Benign. Clinvar id is 3060497.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-140802063-T-C is described in CliVar as Benign. Clinvar id is 3060497.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-140802063-T-C is described in CliVar as Benign. Clinvar id is 3060497.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-140802063-T-C is described in CliVar as Benign. Clinvar id is 3060497.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-140802063-T-C is described in CliVar as Benign. Clinvar id is 3060497.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-140802063-T-C is described in CliVar as Benign. Clinvar id is 3060497.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-140802063-T-C is described in CliVar 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	c.866T>C	p.Ile289Thr	missense_variant	Exon 1 of 4	ENST00000522353.3	NP_061729.1
PCDHA1	NM_018900.4	c.2394+13379T>C		intron_variant	Intron 1 of 3	ENST00000504120.4	NP_061723.1
PCDHA2	NM_018905.3	c.2388+4711T>C		intron_variant	Intron 1 of 3	ENST00000526136.2	NP_061728.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16370 AN: 152130 Hom.: 1015 Cov.: 33

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

GnomAD2 exomes AF: 0.107 AC: 26793 AN: 251414 AF XY: 0.107

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 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.: 88 AF XY: 0.120 AC XY: 87424 AN XY: 727218

African (AFR) AF: 0.0681 AC: 2281 AN: 33480

American (AMR) AF: 0.0545 AC: 2437 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 4173 AN: 26136

East Asian (EAS) AF: 0.0594 AC: 2360 AN: 39700

South Asian (SAS) AF: 0.0823 AC: 7099 AN: 86258

European-Finnish (FIN) AF: 0.188 AC: 10031 AN: 53380

Middle Eastern (MID) AF: 0.0910 AC: 525 AN: 5768

European-Non Finnish (NFE) AF: 0.127 AC: 141366 AN: 1112008

Other (OTH) AF: 0.118 AC: 7113 AN: 60396

GnomAD4 genome AF: 0.107 AC: 16361 AN: 152248 Hom.: 1015 Cov.: 33 AF XY: 0.110 AC XY: 8168 AN XY: 74440

African (AFR) AF: 0.0683 AC: 2840 AN: 41552

American (AMR) AF: 0.0840 AC: 1284 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3472

East Asian (EAS) AF: 0.0710 AC: 368 AN: 5182

South Asian (SAS) AF: 0.0925 AC: 446 AN: 4824

European-Finnish (FIN) AF: 0.188 AC: 1996 AN: 10604

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8535 AN: 68002

Other (OTH) AF: 0.0989 AC: 209 AN: 2114

Alfa AF: 0.117 Hom.: 3869

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

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	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.85
DEOGEN2	Benign	0.026	.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.80	N;N
PhyloP100		-0.095
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	T
GERP RS		2.5
Varity_R		0.13
gMVP		0.068
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3733709; hg19: chr5-140181648; COSMIC: COSV65365779; COSMIC: COSV65365779;