rs34575154

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018900.4(PCDHA1):c.1078A>G(p.Arg360Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,614,210 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.015 ( 64 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 56 hom. )

Consequence

PCDHA1
NM_018900.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.249

Publications

7 publications found

Variant links:

Genes affected

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:

ENSG00000279726 (HGNC:):

ENSG00000279726 links:

PCDHA@ (HGNC:8662):

PCDHA@ links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026019514).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHA1	NM_018900.4 link	c.1078A>G	p.Arg360Gly	missense_variant	Exon 1 of 4	ENST00000504120.4	NP_061723.1	Q9Y5I3-1
PCDHA1	NM_031410.3 link	c.1078A>G	p.Arg360Gly	missense_variant	Exon 1 of 1		NP_113598.1	Q9Y5I3-3
PCDHA1	NM_031411.3 link	c.1078A>G	p.Arg360Gly	missense_variant	Exon 1 of 4		NP_113599.1	Q9Y5I3-2
PCDHA@		n.140787368A>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCDHA1	ENST00000504120.4 link	c.1078A>G	p.Arg360Gly	missense_variant	Exon 1 of 4	1	NM_018900.4	ENSP00000420840.3	Q9Y5I3-1
PCDHA1	ENST00000394633.7 link	c.1078A>G	p.Arg360Gly	missense_variant	Exon 1 of 4	1		ENSP00000378129.3	Q9Y5I3-2
PCDHA1	ENST00000378133.4 link	c.1078A>G	p.Arg360Gly	missense_variant	Exon 1 of 1	6		ENSP00000367373.3	Q9Y5I3-3
ENSG00000279726	ENST00000655235.1 link	n.2144T>C		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2314

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0522

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00621

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.00435

AC:

1095

AN:

251470

AF XY:

0.00319

show subpopulations

Gnomad AFR exome

AF:

0.0551

Gnomad AMR exome

AF:

0.00405

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000281

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00177

AC:

2582

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

1156

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0576

AC:

1927

AN:

33480

American (AMR)

AF:

0.00438

AC:

196

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000203

AC:

226

AN:

1111996

Other (OTH)

AF:

0.00313

AC:

189

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

176

353

529

706

882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0153

AC:

2325

AN:

152332

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1112

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0523

AC:

2175

AN:

41580

American (AMR)

AF:

0.00621

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68022

Other (OTH)

AF:

0.0156

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

113

226

340

453

566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00526

Hom.:

Bravo

AF:

0.0175

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0513

AC:

226

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00517

AC:

628

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

.;.;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.71

T;T;T

MetaRNN

Benign

0.0026

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.5

L;L;L

PhyloP100

0.25

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Benign

0.073

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.76

P;B;P

Vest4

0.093

MVP

0.32

MPC

0.38

ClinPred

0.081

GERP RS

-1.1

Varity_R

0.29

gMVP

0.15

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over