rs61749435
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2
The NM_000350.3(ABCA4):c.2546T>C(p.Val849Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000725 in 1,614,186 control chromosomes in the GnomAD database, including 7 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 0.0035 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00043 ( 4 hom. )
Consequence
ABCA4
NM_000350.3 missense
NM_000350.3 missense
Scores
1
6
11
Clinical Significance
Conservation
PhyloP100: 9.26
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 -6 ACMG points.
PM1
?
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000350.3
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0110659).
BS2
?
High Homozygotes in GnomAd4 at 3 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.2546T>C | p.Val849Ala | missense_variant | 16/50 | ENST00000370225.4 | |
ABCA4 | XM_047416704.1 | c.2324T>C | p.Val775Ala | missense_variant | 15/49 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.2546T>C | p.Val849Ala | missense_variant | 16/50 | 1 | NM_000350.3 | P1 | |
ABCA4 | ENST00000649773.1 | c.2324T>C | p.Val775Ala | missense_variant | 15/19 |
Frequencies
GnomAD3 genomes ? AF: 0.00352 AC: 536AN: 152178Hom.: 3 Cov.: 32
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.00108 AC: 272AN: 251412Hom.: 3 AF XY: 0.000802 AC XY: 109AN XY: 135872
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GnomAD4 exome AF: 0.000432 AC: 631AN: 1461890Hom.: 4 Cov.: 31 AF XY: 0.000415 AC XY: 302AN XY: 727246
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GnomAD4 genome ? AF: 0.00354 AC: 539AN: 152296Hom.: 3 Cov.: 32 AF XY: 0.00325 AC XY: 242AN XY: 74462
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ESP6500AA
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ExAC
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162
Asia WGS
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3478
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:2Other:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 10, 2019 | The ABCA4 c.2546T>C; p.Val849Ala variant (rs61749435) is reported in the literature in multiple individuals affected with Stargardt disease or related retinopathies, although these studies do not agree on the variant’s clinical significance (Cideciyan 2004, Fujinami 2019, Kersten 2018, Lee 2015, Thiadens 2012, Webster 2001). Several affected individuals with the p.Val849Ala variant carried an additional pathogenic variant (Fujinami 2019, Cideciyan 2004), although one individual was found with two other pathogenic ABCA4 variants that may have explained this individual’s disease (Lee 2015). The p.Val849Ala variant is found in the African population with an overall allele frequency of 1.3% (324/24946 alleles, including five homozygotes) in the Genome Aggregation Database. The valine at codon 849 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the p.Val849Ala variant is uncertain at this time. References: Cideciyan AV et al. Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence. Hum Mol Genet. 2004 Mar 1;13(5):525-34. Fujinami K et al. Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8. Br J Ophthalmol. 2019 Mar;103(3):390-397. Kersten E et al. Genetic screening for macular dystrophies in patients clinically diagnosed with dry age-related macular degeneration. Clin Genet. 2018 Dec;94(6):569-574. Lee K et al. High Diagnostic Yield of Whole Exome Sequencing in Participants With Retinal Dystrophies in a Clinical Ophthalmology Setting. Am J Ophthalmol. 2015 Aug;160(2):354-363.e9. Thiadens AA et al. Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. Ophthalmology. 2012 Apr;119(4):819-26. Webster AR et al. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89. - |
not provided, no classification provided | literature only | Retina International | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2019 | This variant is associated with the following publications: (PMID: 11328725, 22264887, 25910913, 30215852, 29925512, 32619608, 15223829, 24011517, 14971589, 20935302, 25066811, 16917483, 14709597) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Severe early-childhood-onset retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Retinal dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 07, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
N;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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