rs11575948

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_018916.4(PCDHGA3):c.460A>C(p.Ile154Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0958 in 1,613,822 control chromosomes in the GnomAD database, including 9,080 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.14 ( 2105 hom., cov: 33)

Exomes 𝑓: 0.091 ( 6975 hom. )

Consequence

PCDHGA3
NM_018916.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.150

Variant links:

Genes affected

PCDHGA3 (HGNC:8701): (protocadherin gamma subfamily A, 3) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

PCDHGA3 links:

PCDHGA2 (HGNC:8700): (protocadherin gamma subfamily A, 2) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

PCDHGA2 links:

PCDHGA1 (HGNC:8696): (protocadherin gamma subfamily A, 1) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

PCDHGA1 links:

PCDHG@ (HGNC:8695):

PCDHG@ 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 (MetaRNN=0.0024713576).

BP6

Variant 5-141344493-A-C is Benign according to our data. Variant chr5-141344493-A-C is described in ClinVar as [Benign]. Clinvar id is 1296894.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHGA3	NM_018916.4 link	c.460A>C	p.Ile154Leu	missense_variant	Exon 1 of 4	ENST00000253812.8	NP_061739.2	Q9Y5H0-1
PCDHGA2	NM_018915.4 link	c.2424+3098A>C		intron_variant	Intron 1 of 3	ENST00000394576.3	NP_061738.1	Q9Y5H1-1
PCDHGA1	NM_018912.3 link	c.2421+11388A>C		intron_variant	Intron 1 of 3	ENST00000517417.3	NP_061735.1	Q9Y5H4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCDHGA3	ENST00000253812.8 link	c.460A>C	p.Ile154Leu	missense_variant	Exon 1 of 4	1	NM_018916.4	ENSP00000253812.7	Q9Y5H0-1
PCDHGA2	ENST00000394576.3 link	c.2424+3098A>C		intron_variant	Intron 1 of 3	1	NM_018915.4	ENSP00000378077.2	Q9Y5H1-1
PCDHGA1	ENST00000517417.3 link	c.2421+11388A>C		intron_variant	Intron 1 of 3	1	NM_018912.3	ENSP00000431083.1	Q9Y5H4-1

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21480

AN:

152072

Hom.:

2094

Cov.:

show subpopulations

Gnomad AFR

AF:

0.280

Gnomad AMI

AF:

0.0374

Gnomad AMR

AF:

0.0856

Gnomad ASJ

AF:

0.0942

Gnomad EAS

AF:

0.0403

Gnomad SAS

AF:

0.0822

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0886

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.0960

AC:

23883

AN:

248740

Hom.:

1549

AF XY:

0.0952

AC XY:

12860

AN XY:

135144

show subpopulations

Gnomad AFR exome

AF:

0.282

Gnomad AMR exome

AF:

0.0574

Gnomad ASJ exome

AF:

0.0890

Gnomad EAS exome

AF:

0.0461

Gnomad SAS exome

AF:

0.0835

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.0902

Gnomad OTH exome

AF:

0.0945

GnomAD4 exome

AF:

0.0910

AC:

133041

AN:

1461632

Hom.:

6975

Cov.:

AF XY:

0.0902

AC XY:

65569

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.281

Gnomad4 AMR exome

AF:

0.0610

Gnomad4 ASJ exome

AF:

0.0904

Gnomad4 EAS exome

AF:

0.0431

Gnomad4 SAS exome

AF:

0.0827

Gnomad4 FIN exome

AF:

0.112

Gnomad4 NFE exome

AF:

0.0873

Gnomad4 OTH exome

AF:

0.0963

GnomAD4 genome

AF:

0.141

AC:

21525

AN:

152190

Hom.:

2105

Cov.:

AF XY:

0.140

AC XY:

10440

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.281

Gnomad4 AMR

AF:

0.0854

Gnomad4 ASJ

AF:

0.0942

Gnomad4 EAS

AF:

0.0404

Gnomad4 SAS

AF:

0.0824

Gnomad4 FIN

AF:

0.121

Gnomad4 NFE

AF:

0.0886

Gnomad4 OTH

AF:

0.127

Alfa

AF:

0.0997

Hom.:

1541

Bravo

AF:

0.146

TwinsUK

AF:

0.0828

AC:

307

ALSPAC

AF:

0.0812

AC:

313

ESP6500AA

AF:

0.266

AC:

991

ESP6500EA

AF:

0.0904

AC:

743

ExAC

AF:

0.0999

AC:

12077

Asia WGS

AF:

0.0750

AC:

262

AN:

3478

EpiCase

AF:

0.0895

EpiControl

AF:

0.0882

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29409727) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.0028

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.20

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.6

N;N

PROVEAN

Benign

2.0

.;N

REVEL

Benign

0.15

Sift

Benign

1.0

.;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.15

MPC

0.42

ClinPred

0.0017

GERP RS

5.7

Varity_R

0.063

gMVP

0.067

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