chr1-94078652-C-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6
The NM_000350.3(ABCA4):c.1294G>A(p.Glu432Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,499,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 26)
Exomes 𝑓: 0.00011 ( 1 hom. )
Consequence
ABCA4
NM_000350.3 missense
NM_000350.3 missense
Scores
3
5
11
Clinical Significance
Conservation
PhyloP100: 3.83
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 Likely_benign. Variant got -3 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000350.3
BP4
Computational evidence support a benign effect (MetaRNN=0.042657107).
BP6
Variant 1-94078652-C-T is Benign according to our data. Variant chr1-94078652-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143072.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.1294G>A | p.Glu432Lys | missense_variant | 10/50 | ENST00000370225.4 | |
LOC124904222 | XR_007066231.1 | n.203-5077C>T | intron_variant, non_coding_transcript_variant | ||||
ABCA4 | XM_047416704.1 | c.1294G>A | p.Glu432Lys | missense_variant | 10/49 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.1294G>A | p.Glu432Lys | missense_variant | 10/50 | 1 | NM_000350.3 | P1 | |
ABCA4 | ENST00000649773.1 | c.1294G>A | p.Glu432Lys | missense_variant | 10/19 |
Frequencies
GnomAD3 genomes AF: 0.000109 AC: 15AN: 137574Hom.: 0 Cov.: 26
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GnomAD3 exomes AF: 0.000155 AC: 39AN: 251490Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135918
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GnomAD4 exome AF: 0.000112 AC: 152AN: 1362088Hom.: 1 Cov.: 38 AF XY: 0.000117 AC XY: 79AN XY: 676196
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GnomAD4 genome AF: 0.000109 AC: 15AN: 137664Hom.: 0 Cov.: 26 AF XY: 0.000168 AC XY: 11AN XY: 65620
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 07, 2024 | - - |
Likely benign, no assertion criteria provided | literature only | Department of Ophthalmology and Visual Sciences Kyoto University | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 15, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed with two other variants in the ABCA4 gene in an individual with Stargardt disease in published literature, but it is not known what combination of the variants occurred on the same (in cis) or on different (in trans) chromosomes (Sung et al., 2019); This variant is associated with the following publications: (PMID: 23424971, 29975949, 33090715, 33301772) - |
Severe early-childhood-onset retinal dystrophy Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.
REVEL
Pathogenic
Sift
Benign
T;.
Sift4G
Benign
T;.
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
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gMVP
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