rs121434542
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_001793.6(CDH3):c.1508G>A(p.Arg503His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R503C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001793.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH3 | NM_001793.6 | c.1508G>A | p.Arg503His | missense_variant | 11/16 | ENST00000264012.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH3 | ENST00000264012.9 | c.1508G>A | p.Arg503His | missense_variant | 11/16 | 1 | NM_001793.6 | P1 | |
CDH3 | ENST00000429102.6 | c.1508G>A | p.Arg503His | missense_variant | 11/16 | 1 | |||
CDH3 | ENST00000542274.5 | c.*1246G>A | 3_prime_UTR_variant, NMD_transcript_variant | 10/15 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251450Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135904
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461802Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727212
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
Congenital hypotrichosis with juvenile macular dystrophy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2002 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDH3 protein function. ClinVar contains an entry for this variant (Variation ID: 17639). This missense change has been observed in individuals with autosomal recessive hypotrichosis with juvenile macular dystrophy (PMID: 12445216, 14708629, 27386845, 30710256). It is commonly reported in individuals of Arab Israeli ancestry (PMID: 14708629). This variant is present in population databases (rs121434542, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 503 of the CDH3 protein (p.Arg503His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at