5-140801382-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_018906.3(PCDHA3):c.185G>T(p.Arg62Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000498 in 1,613,550 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0028 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 3 hom. )

Consequence

PCDHA3
NM_018906.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 8.07

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:

LOC124901089 (HGNC:):

LOC124901089 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019550532).

BP6

Variant 5-140801382-G-T is Benign according to our data. Variant chr5-140801382-G-T is described in ClinVar as [Benign]. Clinvar id is 3039856.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PCDHA3	NM_018906.3 linkuse as main transcript	c.185G>T	p.Arg62Leu	missense_variant	1/4	ENST00000522353.3
PCDHA1	NM_018900.4 linkuse as main transcript	c.2394+12698G>T		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3 linkuse as main transcript	c.2388+4030G>T		intron_variant		ENST00000526136.2
LOC124901089	XR_007058969.1 linkuse as main transcript	n.2940C>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA3	ENST00000522353.3 linkuse as main transcript	c.185G>T	p.Arg62Leu	missense_variant	1/4	1	NM_018906.3	P1	Q9Y5H8-1
PCDHA1	ENST00000504120.4 linkuse as main transcript	c.2394+12698G>T		intron_variant		1	NM_018900.4	P1	Q9Y5I3-1
PCDHA2	ENST00000526136.2 linkuse as main transcript	c.2388+4030G>T		intron_variant		1	NM_018905.3	P1	Q9Y5H9-1
	ENST00000655235.1 linkuse as main transcript	n.658-12528C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

432

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0100

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000740

AC:

185

AN:

250068

Hom.:

AF XY:

0.000576

AC XY:

AN XY:

135516

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000255

AC:

372

AN:

1461196

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

155

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.00960

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.00284

AC:

432

AN:

152354

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

220

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.0100

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.000782

Hom.:

Bravo

AF:

0.00316

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00105

AC:

128

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PCDHA3-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 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

Uncertain

0.45

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D

MetaRNN

Benign

0.020

T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Pathogenic

3.0

M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;D

Vest4

0.78

MVP

0.75

ClinPred

0.068

GERP RS

4.5

Varity_R

0.84

gMVP

0.77

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