5-141355648-G-A

Position:

chr5-141355648-G-A

Variant summary

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

The ENST00000571252.3(PCDHGA4):c.541G>A(p.Ala181Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0947 in 1,613,828 control chromosomes in the GnomAD database, including 8,961 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict 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 0.14 ( 2110 hom., cov: 33)

Exomes 𝑓: 0.090 ( 6851 hom. )

Consequence

PCDHGA4
ENST00000571252.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.40

Variant links:

Genes affected

PCDHGA4 (HGNC:8702): (protocadherin gamma subfamily A, 4) 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]

PCDHGA4 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:

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:

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:

PCDHGB1 (HGNC:8708): (protocadherin gamma subfamily B, 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]

PCDHGB1 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=0.003052801).

BP6

Variant 5-141355648-G-A is Benign according to our data. Variant chr5-141355648-G-A is described in ClinVar as [Benign]. Clinvar id is 1273895.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PCDHGA4	NM_018917.4 linkuse as main transcript	c.541G>A	p.Ala181Thr	missense_variant	1/4	ENST00000571252.3	NP_061740.2
PCDHGA1	NM_018912.3 linkuse as main transcript	c.2421+22543G>A		intron_variant		ENST00000517417.3	NP_061735.1
PCDHGA2	NM_018915.4 linkuse as main transcript	c.2424+14253G>A		intron_variant		ENST00000394576.3	NP_061738.1
PCDHGA3	NM_018916.4 linkuse as main transcript	c.2424+9191G>A		intron_variant		ENST00000253812.8	NP_061739.2
PCDHGB1	NM_018922.3 linkuse as main transcript	c.2409+2979G>A		intron_variant		ENST00000523390.2	NP_061745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHGA4	ENST00000571252.3 linkuse as main transcript	c.541G>A	p.Ala181Thr	missense_variant	1/4	1	NM_018917.4	ENSP00000458570	P1	Q9Y5G9-1
PCDHGA3	ENST00000253812.8 linkuse as main transcript	c.2424+9191G>A		intron_variant		1	NM_018916.4	ENSP00000253812	P1	Q9Y5H0-1
PCDHGA2	ENST00000394576.3 linkuse as main transcript	c.2424+14253G>A		intron_variant		1	NM_018915.4	ENSP00000378077	P1	Q9Y5H1-1
PCDHGA1	ENST00000517417.3 linkuse as main transcript	c.2421+22543G>A		intron_variant		1	NM_018912.3	ENSP00000431083	P1	Q9Y5H4-1
PCDHGB1	ENST00000523390.2 linkuse as main transcript	c.2409+2979G>A		intron_variant		1	NM_018922.3	ENSP00000429273	P1	Q9Y5G3-1

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21427

AN:

152108

Hom.:

2100

Cov.:

show subpopulations

Gnomad AFR

AF:

0.284

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0860

Gnomad ASJ

AF:

0.0925

Gnomad EAS

AF:

0.0401

Gnomad SAS

AF:

0.0821

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0877

Gnomad OTH

AF:

0.130

GnomAD3 exomes

AF:

0.0947

AC:

23590

AN:

248974

Hom.:

1516

AF XY:

0.0938

AC XY:

12679

AN XY:

135100

show subpopulations

Gnomad AFR exome

AF:

0.286

Gnomad AMR exome

AF:

0.0577

Gnomad ASJ exome

AF:

0.0882

Gnomad EAS exome

AF:

0.0462

Gnomad SAS exome

AF:

0.0832

Gnomad FIN exome

AF:

0.108

Gnomad NFE exome

AF:

0.0889

Gnomad OTH exome

AF:

0.0937

GnomAD4 exome

AF:

0.0899

AC:

131363

AN:

1461602

Hom.:

6851

Cov.:

AF XY:

0.0891

AC XY:

64779

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.287

Gnomad4 AMR exome

AF:

0.0613

Gnomad4 ASJ exome

AF:

0.0898

Gnomad4 EAS exome

AF:

0.0431

Gnomad4 SAS exome

AF:

0.0823

Gnomad4 FIN exome

AF:

0.102

Gnomad4 NFE exome

AF:

0.0862

Gnomad4 OTH exome

AF:

0.0959

GnomAD4 genome

AF:

0.141

AC:

21469

AN:

152226

Hom.:

2110

Cov.:

AF XY:

0.139

AC XY:

10369

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.284

Gnomad4 AMR

AF:

0.0859

Gnomad4 ASJ

AF:

0.0925

Gnomad4 EAS

AF:

0.0402

Gnomad4 SAS

AF:

0.0823

Gnomad4 FIN

AF:

0.107

Gnomad4 NFE

AF:

0.0876

Gnomad4 OTH

AF:

0.129

Alfa

AF:

0.0968

Hom.:

1309

Bravo

AF:

0.147

TwinsUK

AF:

0.0814

AC:

302

ALSPAC

AF:

0.0797

AC:

307

ESP6500AA

AF:

0.271

AC:

1017

ESP6500EA

AF:

0.0901

AC:

741

ExAC

AF:

0.0990

AC:

11970

EpiCase

AF:

0.0887

EpiControl

AF:

0.0878

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2019

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

3.4

DANN

Benign

0.73

FATHMM_MKL

Benign

0.0098

LIST_S2

Benign

0.41

T;T

MetaRNN

Benign

0.0031

T;T

MutationTaster

Benign

1.0

P;P;P;P;P

Sift4G

Benign

0.87

T;T

Vest4

0.015

MPC

0.24

GERP RS

2.1

Varity_R

0.046

gMVP

0.11

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