rs1109748
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBA1
The NM_004183.4(BEST1):c.219C>A(p.Ile73Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,614,080 control chromosomes in the GnomAD database, including 31,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.12 ( 2617 hom., cov: 32)
Exomes 𝑓: 0.13 ( 29049 hom. )
Consequence
BEST1
NM_004183.4 synonymous
NM_004183.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.434
Genes affected
BEST1 (HGNC:12703): (bestrophin 1) This gene encodes a member of the bestrophin gene family. This small gene family is characterized by proteins with a highly conserved N-terminus with four to six transmembrane domains. Bestrophins may form chloride ion channels or may regulate voltage-gated L-type calcium-ion channels. Bestrophins are generally believed to form calcium-activated chloride-ion channels in epithelial cells but they have also been shown to be highly permeable to bicarbonate ion transport in retinal tissue. Mutations in this gene are responsible for juvenile-onset vitelliform macular dystrophy (VMD2), also known as Best macular dystrophy, in addition to adult-onset vitelliform macular dystrophy (AVMD) and other retinopathies. Alternative splicing results in multiple variants encoding distinct isoforms.[provided by RefSeq, Nov 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -17 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.13).
BP6
Variant 11-61955173-C-A is Benign according to our data. Variant chr11-61955173-C-A is described in ClinVar as [Benign]. Clinvar id is 99693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61955173-C-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BEST1 | NM_004183.4 | c.219C>A | p.Ile73Ile | synonymous_variant | 3/11 | ENST00000378043.9 | NP_004174.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BEST1 | ENST00000378043.9 | c.219C>A | p.Ile73Ile | synonymous_variant | 3/11 | 1 | NM_004183.4 | ENSP00000367282.4 |
Frequencies
GnomAD3 genomes 0.124 AC: 18910AN: 152104Hom.: 2616 Cov.: 32
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GnomAD3 exomes AF: 0.205 AC: 51573AN: 251400Hom.: 10675 AF XY: 0.213 AC XY: 28881AN XY: 135890
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GnomAD4 exome AF: 0.126 AC: 184849AN: 1461858Hom.: 29049 Cov.: 65 AF XY: 0.137 AC XY: 99437AN XY: 727234
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GnomAD4 genome 0.124 AC: 18915AN: 152222Hom.: 2617 Cov.: 32 AF XY: 0.136 AC XY: 10101AN XY: 74432
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ClinVar
Significance: Benign
Submissions summary: Benign:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4Other:1
| not provided, no classification provided | literature only | Retina International | - | - - |
| Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 32207364) - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
not specified Benign:4
| Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 15, 2014 | - - |
Vitelliform macular dystrophy 2 Benign:2
| Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Autosomal dominant vitreoretinochoroidopathy Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Vitelliform macular dystrophy 2;C2750789:Retinitis pigmentosa 50;C3888099:Autosomal dominant vitreoretinochoroidopathy;C3888198:Autosomal recessive bestrophinopathy Benign:1
| Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 27, 2022 | - - |
Retinal dystrophy Benign:1
| Benign, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Retinitis pigmentosa Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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