5-140801721-CTGAA-C

Position:

• chr5-140801721-CTGAA-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 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 (no stars). 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 no assertion criteria provided 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 -5 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 no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHA3	NM_018906.3	c.526_529del	p.Glu176IlefsTer20	frameshift_variant	1/4	ENST00000522353.3	NP_061729.1
PCDHA1	NM_018900.4	c.2394+13039_2394+13042del		intron_variant		ENST00000504120.4	NP_061723.1
PCDHA2	NM_018905.3	c.2388+4371_2388+4374del		intron_variant		ENST00000526136.2	NP_061728.1
LOC124901089	XR_007058969.1	n.2597_2600del		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHA3	ENST00000522353.3	c.526_529del	p.Glu176IlefsTer20	frameshift_variant	1/4	1	NM_018906.3	ENSP00000429808	P1
PCDHA1	ENST00000504120.4	c.2394+13039_2394+13042del		intron_variant		1	NM_018900.4	ENSP00000420840	P1
PCDHA2	ENST00000526136.2	c.2388+4371_2388+4374del		intron_variant		1	NM_018905.3	ENSP00000431748	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: no assertion criteria provided

Submissions by phenotype

PCDHA3-related disorder Benign:1

Likely benign, no assertion criteria provided

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;