12-69655148-C-T

Position:

• chr12-69655148-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032735.3(BEST3):​c.1766G>A​(p.Arg589Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BEST3 NM_032735.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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]

LOC105369823 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22939223).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BEST3	NM_032735.3	c.1766G>A	p.Arg589Lys	missense_variant	10/10	ENST00000330891.10	NP_116124.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BEST3	ENST00000330891.10	c.1766G>A	p.Arg589Lys	missense_variant	10/10	5	NM_032735.3	ENSP00000332413.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.1766G>A (p.R589K) alteration is located in exon 10 (coding exon 9) of the BEST3 gene. This alteration results from a G to A substitution at nucleotide position 1766, causing the arginine (R) at amino acid position 589 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	0.0025	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.054	.;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.58	T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.5	.;L;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.49	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.092	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.0040	.;B;.
Vest4		0.11
MutPred		0.40		.;Gain of methylation at R589 (P = 0.01);.;
MVP		0.88
MPC		0.054
ClinPred		0.21	T
GERP RS		2.7
Varity_R		0.062
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-70048928; COSMIC: COSV58306588; COSMIC: COSV58306588;