rs3733709

chr5-140802063-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1015 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11542 hom.)
• Consequence: PCDHA3 NM_018906.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0950

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]

LOC124901089 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 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 criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
PCDHA3	NM_018906.3	c.866T>C	p.Ile289Thr	missense_variant	1/4	ENST00000522353.3
PCDHA1	NM_018900.4	c.2394+13379T>C		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+4711T>C		intron_variant		ENST00000526136.2
LOC124901089	XR_007058969.1	n.2259A>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA3	ENST00000522353.3	c.866T>C	p.Ile289Thr	missense_variant	1/4	1	NM_018906.3	P1
PCDHA1	ENST00000504120.4	c.2394+13379T>C		intron_variant		1	NM_018900.4	P1
PCDHA2	ENST00000526136.2	c.2388+4711T>C		intron_variant		1	NM_018905.3	P1
	ENST00000655235.1	n.658-13209A>G		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.107 AC: 26793 AN: 251414 Hom.: 1722 AF XY: 0.107 AC XY: 14521 AN XY: 135878

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

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.: 33 AF XY: 0.110 AC XY: 8168 AN XY: 74440

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: criteria provided, single submitter

Submissions by phenotype

PCDHA3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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
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
MutationTaster	Benign	1.0	P;P;P;P;P;P
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

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