5-140801608-A-G

Position:

• chr5-140801608-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_018906.3(PCDHA3):​c.411A>G​(p.Val137=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,614,172 control chromosomes in the GnomAD database, including 441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (38 hom., cov: 33)
  • Exomes 𝑓: 0.022 (403 hom.)
• Consequence: PCDHA3 NM_018906.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.38

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-140801608-A-G is Benign according to our data. Variant chr5-140801608-A-G is described in ClinVar as [Benign]. Clinvar id is 3042391.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0151 (2296/152278) while in subpopulation NFE AF= 0.0245 (1665/68014). AF 95% confidence interval is 0.0235. There are 38 homozygotes in gnomad4. There are 1108 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA3	NM_018906.3	c.411A>G	p.Val137=	synonymous_variant	1/4	ENST00000522353.3
PCDHA1	NM_018900.4	c.2394+12924A>G		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+4256A>G		intron_variant		ENST00000526136.2
LOC124901089	XR_007058969.1	n.2714T>C		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA3	ENST00000522353.3	c.411A>G	p.Val137=	synonymous_variant	1/4	1	NM_018906.3	P1
PCDHA1	ENST00000504120.4	c.2394+12924A>G		intron_variant		1	NM_018900.4	P1
PCDHA2	ENST00000526136.2	c.2388+4256A>G		intron_variant		1	NM_018905.3	P1
	ENST00000655235.1	n.658-12754T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2296 AN: 152160 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00439

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0245

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0148 AC: 3721 AN: 251468 Hom.: 48 AF XY: 0.0148 AC XY: 2008 AN XY: 135910

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.00870

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00532

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.0219 AC: 32083 AN: 1461894 Hom.: 403 Cov.: 92 AF XY: 0.0212 AC XY: 15416 AN XY: 727248

Gnomad4 AFR exome AF: 0.00364

Gnomad4 AMR exome AF: 0.00854

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00532

Gnomad4 FIN exome AF: 0.0180

Gnomad4 NFE exome AF: 0.0259

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0151 AC: 2296 AN: 152278 Hom.: 38 Cov.: 33 AF XY: 0.0149 AC XY: 1108 AN XY: 74468

Gnomad4 AFR AF: 0.00438

Gnomad4 AMR AF: 0.00954

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.0245

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0200 Hom.: 17

Bravo AF: 0.0139

Asia WGS AF: 0.00202 AC: 7 AN: 3478

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

Feb 20, 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
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.6
DANN	Benign	0.66

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: rs61730634; hg19: chr5-140181193;