20-61852820-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_001794.5(CDH4):c.799G>A(p.Val267Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,976 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000060 ( 1 hom. )
Consequence
CDH4
NM_001794.5 missense
NM_001794.5 missense
Scores
2
10
4
Clinical Significance
Conservation
PhyloP100: 9.65
Genes affected
CDH4 (HGNC:1763): (cadherin 4) This gene is a classical cadherin from the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Based on studies in chicken and mouse, this cadherin is thought to play an important role during brain segmentation and neuronal outgrowth. In addition, a role in kidney and muscle development is indicated. Of particular interest are studies showing stable cis-heterodimers of cadherins 2 and 4 in cotransfected cell lines. Previously thought to interact in an exclusively homophilic manner, this is the first evidence of cadherin heterodimerization. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.796
BS2
?
High AC in GnomAd at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH4 | NM_001794.5 | c.799G>A | p.Val267Ile | missense_variant | 6/16 | ENST00000614565.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH4 | ENST00000614565.5 | c.799G>A | p.Val267Ile | missense_variant | 6/16 | 1 | NM_001794.5 | P1 | |
CDH4 | ENST00000543233.2 | c.577G>A | p.Val193Ile | missense_variant | 5/15 | 2 | |||
CDH4 | ENST00000611855.4 | c.517G>A | p.Val173Ile | missense_variant | 5/15 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152214Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251404Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135884
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GnomAD4 exome AF: 0.0000602 AC: 88AN: 1461762Hom.: 1 Cov.: 31 AF XY: 0.0000523 AC XY: 38AN XY: 727182
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74360
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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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2023 | The c.799G>A (p.V267I) alteration is located in exon 6 (coding exon 6) of the CDH4 gene. This alteration results from a G to A substitution at nucleotide position 799, causing the valine (V) at amino acid position 267 to be replaced by an isoleucine (I). 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
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
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