rs62646863
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBS1BS2
The NM_000350.3(ABCA4):c.466A>G(p.Ile156Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,124 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I156I) has been classified as Likely benign.
Frequency
Consequence
NM_000350.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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ABCA4 | ENST00000370225.4 | c.466A>G | p.Ile156Val | missense_variant | Exon 5 of 50 | 1 | NM_000350.3 | ENSP00000359245.3 | ||
ABCA4 | ENST00000649773.1 | c.466A>G | p.Ile156Val | missense_variant | Exon 5 of 19 | ENSP00000496882.1 |
Frequencies
GnomAD3 genomes AF: 0.00218 AC: 332AN: 152220Hom.: 2 Cov.: 33
GnomAD3 exomes AF: 0.00147 AC: 370AN: 251380Hom.: 1 AF XY: 0.00149 AC XY: 203AN XY: 135860
GnomAD4 exome AF: 0.00197 AC: 2883AN: 1461786Hom.: 9 Cov.: 32 AF XY: 0.00190 AC XY: 1384AN XY: 727212
GnomAD4 genome AF: 0.00218 AC: 332AN: 152338Hom.: 2 Cov.: 33 AF XY: 0.00226 AC XY: 168AN XY: 74496
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:5Other:1
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The I156V variant has been reported in a patient diagnosed with Stargardt disease and was absent from 96 control alleles (Papaioannou et al., 2000). The I156V variant has also been reported as a polymorphism (Riveiro-Alvarez et al.,2009). The NHLBI Exome Sequencing Project and the 1000 Genomes Project reports that I156V was observed in 13/8600 alleles from individuals of European background, in 1/28 alleles from individuals of Spanish background and in 2/196 alleles from individuals of Italian background indicating it may be a rare benign variant in the European population. The I156V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (R152Q, I153L, E161K, G172S) have been reported in the Human Gene Mutation Database in association with ABCA4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. -
The ABCA4 c.466A>G; p.Ile156Val variant (rs62646863) is reported in the literature in individuals affected with retinis pigmentosa, Stargardt disease, or another retinopathy, though it has not been demonstrated to be disease-causing (Ducroq 2002, Oldani 2012, Papaioannou 2000, Passerini 2010, Riveiro-Alvarez 2009, Valverde 2007). While this variant has been described in an affected individual with a second pathogenic variant (Ducroq 2002), it has also been described in healthy controls (Riveiro-Alvarez 2009) and in affected individuals carrying two other pathogenic variants that could explain their symptoms (Oldani 2012, Passerini 2010). The p.Ile156Val variant is found in the Latino population with an overall allele frequency of 0.33% (117/35438 alleles, including one homozygote) in the Genome Aggregation Database. The isoleucine at codon 156 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to conflicting information, the clinical significance of the p.Ile156Val variant is uncertain at this time. References: Ducroq D et al. The ABCA4 gene in autosomal recessive cone-rod dystrophies. Am J Hum Genet. 2002 Dec;71(6):1480-2. Oldani M et al. Clinical and molecular genetic study of 12 Italian families with autosomal recessive Stargardt disease. Genet Mol Res. 2012 Dec 17;11(4):4342-50. Papaioannou M et al. An analysis of ABCR mutations in British patients with recessive retinal dystrophies. Invest Ophthalmol Vis Sci. 2000 Jan;41(1):16-9. Passerini I et al. Novel mutations in of the ABCR gene in Italian patients with Stargardt disease. Eye (Lond). 2010 Jan;24(1):158-64. Riveiro-Alvarez R et al. Frequency of ABCA4 mutations in 278 Spanish controls: an insight into the prevalence of autosomal recessive Stargardt disease. Br J Ophthalmol. 2009 Oct;93(10):1359-64. Valverde D et al. Spectrum of the ABCA4 gene mutations implicated in severe retinopathies in Spanish patients. Invest Ophthalmol Vis Sci. 2007 Mar;48(3):985-90. -
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ABCA4: BP4, BS2 -
The ABCA4 p.Ile156Val variant was identified in 22 of 9152 proband chromosomes (freq=0.0024) from individuals or families with ABCA4-associated diseases, including Stargardt disease, retinitis pigmentosa and retinal dystrophies; the variant was also found in 5 of 348 chromosomes (freq=0.014) from healthy controls (Fujinami_2013_PMID:23982839; Cornelis_2017_PMID:28044389; Oldani_2012_PMID:23096905; Zernant_2011_PMID:21911583; Riviero-Alvarez_2009_PMID:18977788; Ducrog_2002_PMID:12515255; Papaioannou_2000_PMID:10634594, Valverde_2007_PMID:17325136; Passerini_2010_PMID:19265867). The variant was also identified in dbSNP (ID: rs62646863), Cosmic, LOVD 3.0 and ClinVar (classified as a VUS by GeneDx in 2017, EGL Genetic Diagnostics in 2016, Ambry Genetics in 2015, Center for Mendelian Genomics at University Medical Centre Ljubjana in 2017 and classified as likely benign by NIHR Bioresource Rare Diseases, University of Cambridge in 2015). The p.Ile156Val variant was identified in control databases in 408 of 282784 chromosomes (1 homozygous) at a frequency of 0.001443 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 117 of 35438 chromosomes (freq: 0.003302), Other in 18 of 7226 chromosomes (freq: 0.002491), Ashkenazi Jewish in 21 of 10368 chromosomes (freq: 0.002025), European (non-Finnish) in 242 of 129102 chromosomes (freq: 0.001874), African in 4 of 24960 chromosomes (freq: 0.00016), European (Finnish) in 3 of 25122 chromosomes (freq: 0.000119), South Asian in 2 of 30614 chromosomes (freq: 0.000065), and East Asian in 1 of 19954 chromosomes (freq: 0.00005). The I156V variant was identified in 2/29 families with ABCA4-related conditions, one with Stargardt disease and one with cone dystrophy, although the variant was not suggested to be causal in either case (Gonz√°lez-del Pozo_2018_PMID:30190494). The variant was also identified in a proband with early-onset (diagnosed at 14) retinitis pigmentosa, however this variant was suggested to be benign (Hubshman_2018_PMID:29272404). The p.Ile156 residue is not conserved in mammals and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. In addition, the variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
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ABCA4-related disorder Benign:2
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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Inborn genetic diseases Uncertain:1
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Abnormal retinal morphology Uncertain:1
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Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Uncertain:1
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Retinal dystrophy Uncertain:1
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Severe early-childhood-onset retinal dystrophy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at