rs121434552
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP3_ModeratePP5BS2
The NM_000717.5(CA4):c.206G>A(p.Arg69His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000717.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CA4 | NM_000717.5 | c.206G>A | p.Arg69His | missense_variant | 3/8 | ENST00000300900.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CA4 | ENST00000300900.9 | c.206G>A | p.Arg69His | missense_variant | 3/8 | 1 | NM_000717.5 | P1 | |
CA4 | ENST00000591725.1 | c.-65G>A | 5_prime_UTR_variant | 4/5 | 3 | ||||
CA4 | ENST00000585705.5 | n.299G>A | non_coding_transcript_exon_variant | 3/3 | 3 | ||||
CA4 | ENST00000586876.1 | c.206G>A | p.Arg69His | missense_variant, NMD_transcript_variant | 3/6 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251462Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135920
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461678Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727144
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 69 of the CA4 protein (p.Arg69His). This variant is present in population databases (rs121434552, gnomAD 0.02%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 17652713, 20450258). ClinVar contains an entry for this variant (Variation ID: 17609). 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 not expected to disrupt CA4 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CA4 function (PMID: 17652713, 19211803). This variant disrupts the p.Arg69 amino acid residue in CA4. Other variant(s) that disrupt this residue have been observed in individuals with CA4-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Retinitis pigmentosa 17 Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | OMIM | Aug 01, 2007 | - - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at