rs61748526
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP3_StrongPP5_Moderate
The NM_000350.3(ABCA4):āc.223T>Gā(p.Cys75Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,084 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 (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C75R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000350.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.223T>G | p.Cys75Gly | missense_variant | 3/50 | ENST00000370225.4 | |
ABCA4 | XM_047416704.1 | c.223T>G | p.Cys75Gly | missense_variant | 3/49 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.223T>G | p.Cys75Gly | missense_variant | 3/50 | 1 | NM_000350.3 | P1 | |
ABCA4 | ENST00000649773.1 | c.223T>G | p.Cys75Gly | missense_variant | 3/19 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152240Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461844Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727226
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74382
ClinVar
Submissions by phenotype
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 75 of the ABCA4 protein (p.Cys75Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ABCA4-related conditions (PMID: 9973280, 23982839, 30093795). ClinVar contains an entry for this variant (Variation ID: 99122). 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 ABCA4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | Retina International | - | - - |
Severe early-childhood-onset retinal dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at