5-140801382-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_018906.3(PCDHA3):​c.185G>T​(p.Arg62Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000498 in 1,613,550 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 3 hom., cov: 33)
Exomes 𝑓: 0.00025 ( 3 hom. )

Consequence

PCDHA3
NM_018906.3 missense

Scores

5
7
5

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 8.07
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]
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.019550532).
BP6
Variant 5-140801382-G-T is Benign according to our data. Variant chr5-140801382-G-T is described in ClinVar as [Benign]. Clinvar id is 3039856.Status of the report is no_assertion_criteria_provided, 0 stars.
BS2
High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCDHA3NM_018906.3 linkuse as main transcriptc.185G>T p.Arg62Leu missense_variant 1/4 ENST00000522353.3 NP_061729.1
PCDHA1NM_018900.4 linkuse as main transcriptc.2394+12698G>T intron_variant ENST00000504120.4 NP_061723.1
PCDHA2NM_018905.3 linkuse as main transcriptc.2388+4030G>T intron_variant ENST00000526136.2 NP_061728.1
LOC124901089XR_007058969.1 linkuse as main transcriptn.2940C>A non_coding_transcript_exon_variant 2/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCDHA3ENST00000522353.3 linkuse as main transcriptc.185G>T p.Arg62Leu missense_variant 1/41 NM_018906.3 ENSP00000429808 P1Q9Y5H8-1
PCDHA1ENST00000504120.4 linkuse as main transcriptc.2394+12698G>T intron_variant 1 NM_018900.4 ENSP00000420840 P1Q9Y5I3-1
PCDHA2ENST00000526136.2 linkuse as main transcriptc.2388+4030G>T intron_variant 1 NM_018905.3 ENSP00000431748 P1Q9Y5H9-1
ENST00000655235.1 linkuse as main transcriptn.658-12528C>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00284
AC:
432
AN:
152236
Hom.:
3
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0100
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.000740
AC:
185
AN:
250068
Hom.:
2
AF XY:
0.000576
AC XY:
78
AN XY:
135516
show subpopulations
Gnomad AFR exome
AF:
0.0109
Gnomad AMR exome
AF:
0.000260
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:
0.0000265
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000255
AC:
372
AN:
1461196
Hom.:
3
Cov.:
91
AF XY:
0.000213
AC XY:
155
AN XY:
726932
show subpopulations
Gnomad4 AFR exome
AF:
0.00960
Gnomad4 AMR exome
AF:
0.000358
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:
0.00000719
Gnomad4 OTH exome
AF:
0.000431
GnomAD4 genome
AF:
0.00284
AC:
432
AN:
152354
Hom.:
3
Cov.:
33
AF XY:
0.00295
AC XY:
220
AN XY:
74520
show subpopulations
Gnomad4 AFR
AF:
0.0100
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00236
Alfa
AF:
0.000782
Hom.:
0
Bravo
AF:
0.00316
ESP6500AA
AF:
0.0102
AC:
45
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00105
AC:
128
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

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 providedclinical testingPreventionGenetics, part of Exact SciencesDec 27, 2019This 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
AlphaMissense
Uncertain
0.45
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.30
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
.;T
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
D;D
MetaRNN
Benign
0.020
T;T
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Pathogenic
3.0
M;M
MutationTaster
Benign
1.0
D;D;D;D;D;D
PROVEAN
Pathogenic
-6.5
D;D
REVEL
Uncertain
0.43
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
1.0
D;D
Vest4
0.78
MVP
0.75
ClinPred
0.068
T
GERP RS
4.5
Varity_R
0.84
gMVP
0.77

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.

Other links and lift over

dbSNP: rs147415938; hg19: chr5-140180967; API