rs1555099968
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_004183.4(BEST1):c.535A>G(p.Asn179Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N179H) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 31)
Consequence
BEST1
NM_004183.4 missense
NM_004183.4 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 7.12
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 Pathogenic. Variant got 10 ACMG points.
PM1
?
In a transmembrane_region Helical (size 20) in uniprot entity BEST1_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_004183.4
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr11-61956897-A-C is described in Lovd as [Likely_pathogenic].
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.885
PP5
?
Variant 11-61956897-A-G is Pathogenic according to our data. Variant chr11-61956897-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438484.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-61956897-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BEST1 | NM_004183.4 | c.535A>G | p.Asn179Asp | missense_variant | 5/11 | ENST00000378043.9 | |
LOC107984334 | XR_001748245.2 | n.1797T>C | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BEST1 | ENST00000378043.9 | c.535A>G | p.Asn179Asp | missense_variant | 5/11 | 1 | NM_004183.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 39
GnomAD4 exome
Cov.:
39
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Vitelliform macular dystrophy 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | MAGI'S LAB - Medical Genetics Laboratory, MAGI GROUP | Sep 11, 2017 | Assessment via ACMG Guidelines: PM1 Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation PM2 Absent from controls (or at extremely low frequency if recessive) (table 6) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology Likely pathogenic 2 Moderate (PM1-PM6) AND >=2 supporting (PP1-PP5) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Benign
D;T;D
Sift4G
Benign
T;T;T
Polyphen
D;D;P
Vest4
MutPred
Loss of MoRF binding (P = 0.0659);.;.;
MVP
MPC
1.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at