11-61959909-GGATGA-G
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_004183.4(BEST1):c.971_975delAGATG(p.Glu324AlafsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
BEST1
NM_004183.4 frameshift
NM_004183.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.21
Publications
0 publications found
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]
FTH1 (HGNC:3976): (ferritin heavy chain 1) This gene encodes the heavy subunit of ferritin, the major intracellular iron storage protein in prokaryotes and eukaryotes. It is composed of 24 subunits of the heavy and light ferritin chains. Variation in ferritin subunit composition may affect the rates of iron uptake and release in different tissues. A major function of ferritin is the storage of iron in a soluble and nontoxic state. Defects in ferritin proteins are associated with several neurodegenerative diseases. This gene has multiple pseudogenes. Several alternatively spliced transcript variants have been observed, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]
FTH1 Gene-Disease associations (from GenCC):
- hemochromatosis type 5Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, ClinGen
- neurodegeneration with brain iron accumulation 9Inheritance: AD Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-61959909-GGATGA-G is Pathogenic according to our data. Variant chr11-61959909-GGATGA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 3037061.Status of the report is no_assertion_criteria_provided, 0 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_004183.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BEST1 | NM_004183.4 | MANE Select | c.971_975delAGATG | p.Glu324AlafsTer15 | frameshift | Exon 9 of 11 | NP_004174.1 | O76090-1 | |
| BEST1 | NM_001440571.1 | c.971_975delAGATG | p.Glu324AlafsTer15 | frameshift | Exon 9 of 10 | NP_001427500.1 | |||
| BEST1 | NM_001440572.1 | c.890_894delAGATG | p.Glu297AlafsTer15 | frameshift | Exon 8 of 9 | NP_001427501.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BEST1 | ENST00000378043.9 | TSL:1 MANE Select | c.971_975delAGATG | p.Glu324AlafsTer15 | frameshift | Exon 9 of 11 | ENSP00000367282.4 | O76090-1 | |
| BEST1 | ENST00000449131.6 | TSL:1 | c.791_795delAGATG | p.Glu264AlafsTer15 | frameshift | Exon 8 of 9 | ENSP00000399709.2 | O76090-3 | |
| BEST1 | ENST00000526988.1 | TSL:2 | c.856_860delAGATG | p.Arg286HisfsTer80 | frameshift | Exon 8 of 9 | ENSP00000433195.1 | B7Z1N8 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461496Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726994 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461496
Hom.:
AF XY:
AC XY:
0
AN XY:
726994
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33474
American (AMR)
AF:
AC:
0
AN:
44682
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26126
East Asian (EAS)
AF:
AC:
0
AN:
39684
South Asian (SAS)
AF:
AC:
0
AN:
86128
European-Finnish (FIN)
AF:
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111864
Other (OTH)
AF:
AC:
0
AN:
60374
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
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0
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:no assertion criteria provided
Pathogenic
VUS
Benign
Condition
1
-
-
BEST1-related disorder (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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