5-140801509-C-T

Position:

chr5-140801509-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_018906.3(PCDHA3):c.312C>T(p.Ile104=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,614,194 control chromosomes in the GnomAD database, including 542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.019 ( 51 hom., cov: 33)

Exomes 𝑓: 0.023 ( 491 hom. )

Consequence

PCDHA3
NM_018906.3 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.751

Variant links:

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]

PCDHA3 links:

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]

PCDHA1 links:

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]

PCDHA2 links:

LOC124901089 (HGNC:):

LOC124901089 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 5-140801509-C-T is Benign according to our data. Variant chr5-140801509-C-T is described in ClinVar as [Benign]. Clinvar id is 3037513.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.751 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.019 (2902/152362) while in subpopulation NFE AF= 0.0304 (2069/68034). AF 95% confidence interval is 0.0293. There are 51 homozygotes in gnomad4. There are 1381 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 51 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PCDHA3	NM_018906.3 linkuse as main transcript	c.312C>T	p.Ile104=	synonymous_variant	1/4	ENST00000522353.3	NP_061729.1
PCDHA1	NM_018900.4 linkuse as main transcript	c.2394+12825C>T		intron_variant		ENST00000504120.4	NP_061723.1
PCDHA2	NM_018905.3 linkuse as main transcript	c.2388+4157C>T		intron_variant		ENST00000526136.2	NP_061728.1
LOC124901089	XR_007058969.1 linkuse as main transcript	n.2813G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHA3	ENST00000522353.3 linkuse as main transcript	c.312C>T	p.Ile104=	synonymous_variant	1/4	1	NM_018906.3	ENSP00000429808	P1	Q9Y5H8-1
PCDHA1	ENST00000504120.4 linkuse as main transcript	c.2394+12825C>T		intron_variant		1	NM_018900.4	ENSP00000420840	P1	Q9Y5I3-1
PCDHA2	ENST00000526136.2 linkuse as main transcript	c.2388+4157C>T		intron_variant		1	NM_018905.3	ENSP00000431748	P1	Q9Y5H9-1
	ENST00000655235.1 linkuse as main transcript	n.658-12655G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0191

AC:

2902

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00335

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.0392

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0304

Gnomad OTH

AF:

0.0144

GnomAD3 exomes

AF:

0.0195

AC:

4912

AN:

251486

Hom.:

AF XY:

0.0192

AC XY:

2607

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00338

Gnomad AMR exome

AF:

0.00781

Gnomad ASJ exome

AF:

0.0109

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00483

Gnomad FIN exome

AF:

0.0425

Gnomad NFE exome

AF:

0.0289

Gnomad OTH exome

AF:

0.0199

GnomAD4 exome

AF:

0.0229

AC:

33437

AN:

1461832

Hom.:

491

Cov.:

AF XY:

0.0226

AC XY:

16407

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00358

Gnomad4 AMR exome

AF:

0.00812

Gnomad4 ASJ exome

AF:

0.0108

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00511

Gnomad4 FIN exome

AF:

0.0420

Gnomad4 NFE exome

AF:

0.0260

Gnomad4 OTH exome

AF:

0.0173

GnomAD4 genome

AF:

0.0190

AC:

2902

AN:

152362

Hom.:

Cov.:

AF XY:

0.0185

AC XY:

1381

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00334

Gnomad4 AMR

AF:

0.0116

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00517

Gnomad4 FIN

AF:

0.0392

Gnomad4 NFE

AF:

0.0304

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0251

Hom.:

Bravo

AF:

0.0149

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0225

EpiControl

AF:

0.0215

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PCDHA3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 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

-0.56

CADD

Benign

DANN

Benign

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over