Menu
GeneBe

5-140801509-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_018906.3(PCDHA3):c.312C>T(p.Ile104=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,614,194 control chromosomes in the GnomAD database, including 542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.019 ( 51 hom., cov: 33)
Exomes 𝑓: 0.023 ( 491 hom. )

Consequence

PCDHA3
NM_018906.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.751
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.56).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 5-140801509-C-T is Benign according to our data. Variant chr5-140801509-C-T is described in ClinVar as [Benign]. Clinvar id is 3037513.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.751 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.019 (2902/152362) while in subpopulation NFE AF= 0.0304 (2069/68034). AF 95% confidence interval is 0.0293. There are 51 homozygotes in gnomad4. There are 1381 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 51 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCDHA3NM_018906.3 linkuse as main transcriptc.312C>T p.Ile104= synonymous_variant 1/4 ENST00000522353.3
PCDHA1NM_018900.4 linkuse as main transcriptc.2394+12825C>T intron_variant ENST00000504120.4
PCDHA2NM_018905.3 linkuse as main transcriptc.2388+4157C>T intron_variant ENST00000526136.2
LOC124901089XR_007058969.1 linkuse as main transcriptn.2813G>A non_coding_transcript_exon_variant 2/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCDHA3ENST00000522353.3 linkuse as main transcriptc.312C>T p.Ile104= synonymous_variant 1/41 NM_018906.3 P1Q9Y5H8-1
PCDHA1ENST00000504120.4 linkuse as main transcriptc.2394+12825C>T intron_variant 1 NM_018900.4 P1Q9Y5I3-1
PCDHA2ENST00000526136.2 linkuse as main transcriptc.2388+4157C>T intron_variant 1 NM_018905.3 P1Q9Y5H9-1
ENST00000655235.1 linkuse as main transcriptn.658-12655G>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0191
AC:
2902
AN:
152244
Hom.:
51
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00335
Gnomad AMI
AF:
0.00329
Gnomad AMR
AF:
0.0116
Gnomad ASJ
AF:
0.0121
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00517
Gnomad FIN
AF:
0.0392
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0304
Gnomad OTH
AF:
0.0144
GnomAD3 exomes
AF:
0.0195
AC:
4912
AN:
251486
Hom.:
90
AF XY:
0.0192
AC XY:
2607
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00338
Gnomad AMR exome
AF:
0.00781
Gnomad ASJ exome
AF:
0.0109
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00483
Gnomad FIN exome
AF:
0.0425
Gnomad NFE exome
AF:
0.0289
Gnomad OTH exome
AF:
0.0199
GnomAD4 exome
AF:
0.0229
AC:
33437
AN:
1461832
Hom.:
491
Cov.:
93
AF XY:
0.0226
AC XY:
16407
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.00358
Gnomad4 AMR exome
AF:
0.00812
Gnomad4 ASJ exome
AF:
0.0108
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00511
Gnomad4 FIN exome
AF:
0.0420
Gnomad4 NFE exome
AF:
0.0260
Gnomad4 OTH exome
AF:
0.0173
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0190
AC:
2902
AN:
152362
Hom.:
51
Cov.:
33
AF XY:
0.0185
AC XY:
1381
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.00334
Gnomad4 AMR
AF:
0.0116
Gnomad4 ASJ
AF:
0.0121
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00517
Gnomad4 FIN
AF:
0.0392
Gnomad4 NFE
AF:
0.0304
Gnomad4 OTH
AF:
0.0142
Alfa
AF:
0.0251
Hom.:
31
Bravo
AF:
0.0149
Asia WGS
AF:
0.00462
AC:
16
AN:
3478
EpiCase
AF:
0.0225
EpiControl
AF:
0.0215

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

PCDHA3-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 23, 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
BayesDel_noAF
Benign
-0.56
Cadd
Benign
12
Dann
Benign
0.90

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: rs251382; hg19: chr5-140181094; COSMIC: COSV65371622; COSMIC: COSV65371622; API