chr12-69672889-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_032735.3(BEST3):āc.944T>Cā(p.Leu315Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000994 in 1,609,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000053 ( 0 hom., cov: 33)
Exomes š: 0.0000055 ( 0 hom. )
Consequence
BEST3
NM_032735.3 missense
NM_032735.3 missense
Scores
12
5
1
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
BEST3 (HGNC:17105): (bestrophin 3) BEST3 belongs to the bestrophin family of anion channels, which includes BEST1 (MIM 607854), the gene mutant in vitelliform macular dystrophy (VMD; MIM 153700), and 2 other BEST1-like genes, BEST2 (MIM 607335) and BEST4 (MIM 607336). Bestrophins are transmembrane (TM) proteins that share a homology region containing a high content of aromatic residues, including an invariant arg-phe-pro (RFP) motif. The bestrophin genes share a conserved gene structure, with almost identical sizes of the 8 RFP-TM domain-encoding exons and highly conserved exon-intron boundaries. Each of the 4 bestrophin genes has a unique 3-prime end of variable length (Stohr et al., 2002 [PubMed 12032738]; Tsunenari et al., 2003 [PubMed 12907679]).[supplied by OMIM, Mar 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.922
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BEST3 | NM_032735.3 | c.944T>C | p.Leu315Ser | missense_variant | 8/10 | ENST00000330891.10 | |
LOC105369823 | XR_007063357.1 | n.312-15652A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BEST3 | ENST00000330891.10 | c.944T>C | p.Leu315Ser | missense_variant | 8/10 | 5 | NM_032735.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152228Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000812 AC: 2AN: 246246Hom.: 0 AF XY: 0.00000749 AC XY: 1AN XY: 133552
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GnomAD4 exome AF: 0.00000549 AC: 8AN: 1456882Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2AN XY: 724684
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 26, 2023 | The c.944T>C (p.L315S) alteration is located in exon 8 (coding exon 7) of the BEST3 gene. This alteration results from a T to C substitution at nucleotide position 944, causing the leucine (L) at amino acid position 315 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;.
Polyphen
P;.;D;.;D;.
Vest4
MVP
MPC
0.33
ClinPred
D
GERP RS
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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