chr5-140807632-G-C
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_018907.4(PCDHA4):c.445G>C(p.Asp149His) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
PCDHA4
NM_018907.4 missense
NM_018907.4 missense
Scores
1
2
15
Clinical Significance
Conservation
PhyloP100: 6.85
Genes affected
PCDHA4 (HGNC:8670): (protocadherin alpha 4) 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]
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]
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.33112198).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PCDHA4 | NM_018907.4 | c.445G>C | p.Asp149His | missense_variant | Exon 1 of 4 | ENST00000530339.2 | NP_061730.1 | |
| PCDHA1 | NM_018900.4 | c.2394+18948G>C | intron_variant | Intron 1 of 3 | ENST00000504120.4 | NP_061723.1 | ||
| PCDHA3 | NM_018906.3 | c.2394+4041G>C | intron_variant | Intron 1 of 3 | ENST00000522353.3 | NP_061729.1 | ||
| PCDHA2 | NM_018905.3 | c.2388+10280G>C | intron_variant | Intron 1 of 3 | ENST00000526136.2 | NP_061728.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PCDHA4 | ENST00000530339.2 | c.445G>C | p.Asp149His | missense_variant | Exon 1 of 4 | 1 | NM_018907.4 | ENSP00000435300.1 | ||
| PCDHA1 | ENST00000504120.4 | c.2394+18948G>C | intron_variant | Intron 1 of 3 | 1 | NM_018900.4 | ENSP00000420840.3 | |||
| PCDHA3 | ENST00000522353.3 | c.2394+4041G>C | intron_variant | Intron 1 of 3 | 1 | NM_018906.3 | ENSP00000429808.2 | |||
| PCDHA2 | ENST00000526136.2 | c.2388+10280G>C | intron_variant | Intron 1 of 3 | 1 | NM_018905.3 | ENSP00000431748.1 |
Frequencies
GnomAD3 genomes 0.0000526 AC: 8AN: 152214Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251490Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135922
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GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461886Hom.: 0 Cov.: 125 AF XY: 0.0000289 AC XY: 21AN XY: 727240
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GnomAD4 genome 0.0000526 AC: 8AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74372
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Dec 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.445G>C (p.D149H) alteration is located in exon 1 (coding exon 1) of the PCDHA4 gene. This alteration results from a G to C substitution at nucleotide position 445, causing the aspartic acid (D) at amino acid position 149 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L;.;L
PROVEAN
Pathogenic
.;.;D;D
REVEL
Benign
Sift
Benign
.;.;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
0.12, 0.14, 0.081
.;B;B;B
Vest4
0.30, 0.46, 0.46
MVP
ClinPred
T
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at