5-140786609-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018900.4(PCDHA1):c.319G>A(p.Glu107Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PCDHA1
NM_018900.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.687

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PCDHA1	NM_018900.4 linkuse as main transcript	c.319G>A	p.Glu107Lys	missense_variant	1/4	ENST00000504120.4
PCDHA1	NM_031410.2 linkuse as main transcript	c.319G>A	p.Glu107Lys	missense_variant	1/1
PCDHA1	NM_031411.3 linkuse as main transcript	c.319G>A	p.Glu107Lys	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHA1	ENST00000504120.4 linkuse as main transcript	c.319G>A	p.Glu107Lys	missense_variant	1/4	1	NM_018900.4	P1	Q9Y5I3-1
PCDHA1	ENST00000394633.7 linkuse as main transcript	c.319G>A	p.Glu107Lys	missense_variant	1/4	1			Q9Y5I3-2
	ENST00000655235.1 linkuse as main transcript	n.2903C>T		non_coding_transcript_exon_variant	2/2
PCDHA1	ENST00000378133.4 linkuse as main transcript	c.319G>A	p.Glu107Lys	missense_variant	1/1				Q9Y5I3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251476

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2023

The c.319G>A (p.E107K) alteration is located in exon 1 (coding exon 1) of the PCDHA1 gene. This alteration results from a G to A substitution at nucleotide position 319, causing the glutamic acid (E) at amino acid position 107 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.46

Cadd

Uncertain

Dann

Pathogenic

1.0

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.71

D;D;D

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.3

M;M;M

MutationTaster

Benign

0.84

N;N;N

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.029

D;T;T

Polyphen

0.99

D;D;D

Vest4

0.29

MutPred

0.75

Gain of ubiquitination at E107 (P = 0.0211);Gain of ubiquitination at E107 (P = 0.0211);Gain of ubiquitination at E107 (P = 0.0211);

MVP

0.59

MPC

1.1

ClinPred

0.97

GERP RS

4.3

Varity_R

0.71

gMVP

0.54

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