rs61748549
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting
The NM_000350.3(ABCA4):c.1140T>A(p.Asn380Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,614,226 control chromosomes in the GnomAD database, including 2 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 0.00062 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00070 ( 2 hom. )
Consequence
ABCA4
NM_000350.3 missense
NM_000350.3 missense
Scores
12
7
Clinical Significance
Conservation
PhyloP100: 2.47
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 -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.050882727).
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.1140T>A | p.Asn380Lys | missense_variant | 9/50 | ENST00000370225.4 | |
LOC124904222 | XR_007066231.1 | n.203-4308A>T | intron_variant, non_coding_transcript_variant | ||||
ABCA4 | XM_047416704.1 | c.1140T>A | p.Asn380Lys | missense_variant | 9/49 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.1140T>A | p.Asn380Lys | missense_variant | 9/50 | 1 | NM_000350.3 | P1 | |
ABCA4 | ENST00000649773.1 | c.1140T>A | p.Asn380Lys | missense_variant | 9/19 |
Frequencies
GnomAD3 genomes AF: 0.000611 AC: 93AN: 152216Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000549 AC: 138AN: 251378Hom.: 0 AF XY: 0.000530 AC XY: 72AN XY: 135846
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GnomAD4 exome AF: 0.000696 AC: 1017AN: 1461892Hom.: 2 Cov.: 34 AF XY: 0.000693 AC XY: 504AN XY: 727248
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GnomAD4 genome AF: 0.000617 AC: 94AN: 152334Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51AN XY: 74492
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:8Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not provided, no classification provided | literature only | Retina International | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2023 | Identified in patients with Stargardt disease and retinitis pigmentosa in published literature, however a second ABCA4 variant was not identified in these cases (Webster et al., 2001; Valverde et al., 2006; Valverde et al., 2007; Smaragda et al., 2018); Identified in a patient with retinitis pigmentosa in published literature who also had two loss-of-function variants in the CEP290 gene (Eisenberger et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18977788, 16917483, 17325136, 14709597, 34426522, 32641690, 29854428, 26355662, 11328725, 35836572, 32000842, 24265693) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 17, 2016 | - - |
ABCA4-related disorder Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 27, 2024 | The ABCA4 c.1140T>A variant is predicted to result in the amino acid substitution p.Asn380Lys. This variant has been reported in multiple individuals with autosomal recessive retinal dystrophies (see for example, Table S1, Patel et al. 2015. PubMed ID: 26355662; Table 1, Riveiro-Alvarez et al 2013. PubMed ID: 23755871; Table S4, Maltese et al. 2022. PubMed ID: 35836572). However, in Riveiro-Alvarez et al. this variant was reported in cis with another variant as c.[1140T>A; 5395A>G] (p.[Asn380Lys; Asn1799Asp]). This variant is reported in 0.091% of alleles in individuals of European (non-Finnish) descent in gnomAD, indicating it is relatively common. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Autosomal recessive retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Faculty of Health Sciences, Beirut Arab University | Sep 10, 2015 | - - |
Severe early-childhood-onset retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 30, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
B;.
Vest4
MutPred
Gain of catalytic residue at N380 (P = 0.0069);Gain of catalytic residue at N380 (P = 0.0069);
MVP
MPC
ClinPred
T
GERP RS
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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