rs61752406
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The ENST00000370225.4(ABCA4):c.2564G>A(p.Trp855Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000124 in 1,613,922 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
ABCA4
ENST00000370225.4 stop_gained
ENST00000370225.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.95
Genes affected
ABCA4 (HGNC:34): (ATP binding cassette subfamily A member 4) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is a retina-specific ABC transporter with N-retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essental molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile-onset macular degeneration. Mutations in this gene are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. [provided by RefSeq, Sep 2019]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 1-94055134-C-T is Pathogenic according to our data. Variant chr1-94055134-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 99144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94055134-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94055134-C-T is described in Lovd as [Pathogenic]. Variant chr1-94055134-C-T is described in Lovd as [Pathogenic]. Variant chr1-94055134-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.2564G>A | p.Trp855Ter | stop_gained | 16/50 | ENST00000370225.4 | NP_000341.2 | |
ABCA4 | XM_047416704.1 | c.2342G>A | p.Trp781Ter | stop_gained | 15/49 | XP_047272660.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.2564G>A | p.Trp855Ter | stop_gained | 16/50 | 1 | NM_000350.3 | ENSP00000359245 | P1 | |
ABCA4 | ENST00000649773.1 | c.2342G>A | p.Trp781Ter | stop_gained | 15/19 | ENSP00000496882 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152046Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251404Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135872
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727240
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152046Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74250
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 30, 2023 | This sequence change creates a premature translational stop signal (p.Trp855*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs61752406, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with ABCA4-related disease (PMID: 12192456, 17982420, 25312043, 28118664). ClinVar contains an entry for this variant (Variation ID: 99144). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 30, 2020 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10958763, 12192456, 22247458, 27939946, 29701254, 28118664, 23891399, 17982420, 26593885, 26551331, 29925512, 29386879, 32467599) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 31, 2017 | - - |
not provided, no classification provided | literature only | Retina International | - | - - |
Retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 12, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2021 | - - |
Severe early-childhood-onset retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2016 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
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