rs149071415
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_000350.3(ABCA4):āc.2813T>Cā(p.Phe938Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,060 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000350.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.2813T>C | p.Phe938Ser | missense_variant | 19/50 | ENST00000370225.4 | |
ABCA4 | XM_047416704.1 | c.2591T>C | p.Phe864Ser | missense_variant | 18/49 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.2813T>C | p.Phe938Ser | missense_variant | 19/50 | 1 | NM_000350.3 | P1 | |
ABCA4 | ENST00000649773.1 | c.2591T>C | p.Phe864Ser | missense_variant | 18/19 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251438Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135888
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727248
GnomAD4 genome ? AF: 0.0000789 AC: 12AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74342
ClinVar
Submissions by phenotype
Retinal dystrophy Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 11, 2019 | - - |
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 938 of the ABCA4 protein (p.Phe938Ser). This variant is present in population databases (rs149071415, gnomAD 0.05%). This missense change has been observed in individuals with ABCA4-related conditions (PMID: 28041643, 29925512; Invitae). ClinVar contains an entry for this variant (Variation ID: 438091). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 07, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32581362, 29925512, 28041643) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at