5-140801379-C-A

Position:

• chr5-140801379-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
PCDHA3	NM_018906.3	c.182C>A	p.Pro61Gln	missense_variant	1/4	ENST00000522353.3	NP_061729.1
PCDHA1	NM_018900.4	c.2394+12695C>A		intron_variant		ENST00000504120.4	NP_061723.1
PCDHA2	NM_018905.3	c.2388+4027C>A		intron_variant		ENST00000526136.2	NP_061728.1
LOC124901089	XR_007058969.1	n.2943G>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHA3	ENST00000522353.3	c.182C>A	p.Pro61Gln	missense_variant	1/4	1	NM_018906.3	ENSP00000429808	P1
PCDHA1	ENST00000504120.4	c.2394+12695C>A		intron_variant		1	NM_018900.4	ENSP00000420840	P1
PCDHA2	ENST00000526136.2	c.2388+4027C>A		intron_variant		1	NM_018905.3	ENSP00000431748	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: no assertion criteria provided

Submissions by phenotype

PCDHA3-related disorder Benign:1

Benign, no assertion criteria provided

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
DEOGEN2	Benign	0.15	.;T
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;