5-140801379-C-A

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.182C>A(p.Pro61Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00993 in 1,613,474 control chromosomes in the GnomAD database, including 1,346 homozygotes. In-silico tool predicts 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 0.054 (721 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (625 hom.)
• Consequence: PCDHA3 NM_018906.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.253

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=0.0028607547).
• BP6: Variant 5-140801379-C-A is Benign according to our data. Variant chr5-140801379-C-A is described in ClinVar as [Benign]. Clinvar id is 3056261.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHA3	NM_018906.3	c.182C>A	p.Pro61Gln	missense_variant	1/4	ENST00000522353.3
PCDHA1	NM_018900.4	c.2394+12695C>A		intron_variant		ENST00000504120.4
PCDHA2	NM_018905.3	c.2388+4027C>A		intron_variant		ENST00000526136.2
LOC124901089	XR_007058969.1	n.2943G>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA3	ENST00000522353.3	c.182C>A	p.Pro61Gln	missense_variant	1/4	1	NM_018906.3	P1
PCDHA1	ENST00000504120.4	c.2394+12695C>A		intron_variant		1	NM_018900.4	P1
PCDHA2	ENST00000526136.2	c.2388+4027C>A		intron_variant		1	NM_018905.3	P1
	ENST00000655235.1	n.658-12525G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 8147 AN: 152170 Hom.: 718 Cov.: 33

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.0363

GnomAD3 exomes AF: 0.0139 AC: 3483 AN: 250062 Hom.: 278 AF XY: 0.0102 AC XY: 1383 AN XY: 135504

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.00819

GnomAD4 exome AF: 0.00537 AC: 7851 AN: 1461186 Hom.: 625 Cov.: 91 AF XY: 0.00467 AC XY: 3396 AN XY: 726922

Gnomad4 AFR exome AF: 0.185

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000285

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.0536 AC: 8170 AN: 152288 Hom.: 721 Cov.: 33 AF XY: 0.0519 AC XY: 3869 AN XY: 74488

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.0197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.00602 Hom.: 22

Bravo AF: 0.0608

ESP6500AA AF: 0.179 AC: 789

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.0172 AC: 2087

EpiCase AF: 0.000545

EpiControl AF: 0.000593

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

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	Benign	0.22
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	2.2e-11	P;P;P;P;P;P
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Benign	0.12
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.080	T;T
Polyphen		0.79	P;P
Vest4		0.28
ClinPred		0.065	T
GERP RS		3.6
Varity_R		0.33
gMVP		0.40

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: rs7731327; hg19: chr5-140180964;