5-140801721-CTGAA-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_018906.3(PCDHA3):c.526_529del(p.Glu176IlefsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,614,106 control chromosomes in the GnomAD database, including 133 homozygotes. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0096 (11 hom., cov: 33)
  • Exomes 𝑓: 0.011 (122 hom.)
• Consequence: PCDHA3 NM_018906.3 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.98

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 5-140801721-CTGAA-C is Benign according to our data. Variant chr5-140801721-CTGAA-C is described in ClinVar as [Likely_benign]. Clinvar id is 3055470.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA3	NM_018906.3	c.526_529del	p.Glu176IlefsTer20	frameshift_variant	1/4	ENST00000522353.3
PCDHA1	NM_018900.4	c.2394+13039_2394+13042del		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+4371_2388+4374del		intron_variant		ENST00000526136.2
LOC124901089	XR_007058969.1	n.2597_2600del		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA3	ENST00000522353.3	c.526_529del	p.Glu176IlefsTer20	frameshift_variant	1/4	1	NM_018906.3	P1
PCDHA1	ENST00000504120.4	c.2394+13039_2394+13042del		intron_variant		1	NM_018900.4	P1
PCDHA2	ENST00000526136.2	c.2388+4371_2388+4374del		intron_variant		1	NM_018905.3	P1
	ENST00000655235.1	n.658-12871_658-12868del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00960 AC: 1461 AN: 152134 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0362

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00963 AC: 2421 AN: 251358 Hom.: 28 AF XY: 0.00972 AC XY: 1321 AN XY: 135884

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0352

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0114 AC: 16698 AN: 1461854 Hom.: 122 AF XY: 0.0110 AC XY: 8001 AN XY: 727220

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00490

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0344

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.00954

GnomAD4 genome AF: 0.00960 AC: 1461 AN: 152252 Hom.: 11 Cov.: 33 AF XY: 0.0102 AC XY: 758 AN XY: 74428

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0362

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00932 Hom.: 0

Bravo AF: 0.00705

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.0107

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PCDHA3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as likely 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

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: rs141677026; hg19: chr5-140181306;