12-69655784-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032735.3(BEST3):c.1130A>C(p.Glu377Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E377G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BEST3 NM_032735.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3335628).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BEST3	NM_032735.3	c.1130A>C	p.Glu377Ala	missense_variant	10/10	ENST00000330891.10
LOC105369823	XR_007063357.1	n.311+16770T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BEST3	ENST00000330891.10	c.1130A>C	p.Glu377Ala	missense_variant	10/10	5	NM_032735.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

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

Jul 06, 2021

The c.1130A>C (p.E377A) alteration is located in exon 10 (coding exon 9) of the BEST3 gene. This alteration results from a A to C substitution at nucleotide position 1130, causing the glutamic acid (E) at amino acid position 377 to be replaced by an alanine (A). 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	0.093
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	0.080
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Pathogenic	0.89	D
MutationTaster	Benign	0.60	D;D;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.081	.;B;.
Vest4		0.24
MutPred		0.43		.;Gain of loop (P = 0.0166);.;
MVP		0.94
MPC		0.066
ClinPred		0.91	D
GERP RS		5.6
Varity_R		0.18
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-70049564;