12-69643740-G-A

Position:

• chr12-69643740-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001282614.2(BEST3):​c.1148C>T​(p.Pro383Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 714,342 control chromosomes in the GnomAD database, including 4,589 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1247 hom., cov: 32)
  • Exomes 𝑓: 0.099 (3342 hom.)
• Consequence: BEST3 NM_001282614.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.106

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004787594).
• BP6: Variant 12-69643740-G-A is Benign according to our data. Variant chr12-69643740-G-A is described in ClinVar as [Benign]. Clinvar id is 1234899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BEST3	NM_001282614.2	c.1148C>T	p.Pro383Leu	missense_variant	10/10		NP_001269543.1
LOC105369823	XR_007063357.1	n.311+4726G>A		intron_variant
LOC105369823	XR_007063358.1	n.311+4726G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BEST3	ENST00000331471.8	c.1148C>T	p.Pro383Leu	missense_variant	10/10	1		ENSP00000329064.4
BEST3	ENST00000547208.5	n.*166C>T		non_coding_transcript_exon_variant	7/7	5		ENSP00000449868.1
BEST3	ENST00000547208.5	n.*166C>T		3_prime_UTR_variant	7/7	5		ENSP00000449868.1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18179 AN: 152026 Hom.: 1252 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0602

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0935

Gnomad OTH AF: 0.0943

GnomAD3 exomes AF: 0.0982 AC: 14474 AN: 147416 Hom.: 948 AF XY: 0.0977 AC XY: 7766 AN XY: 79458

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.0441

Gnomad ASJ exome AF: 0.0411

Gnomad EAS exome AF: 0.233

Gnomad SAS exome AF: 0.0844

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.0868

Gnomad OTH exome AF: 0.0837

GnomAD4 exome AF: 0.0993 AC: 55815 AN: 562198 Hom.: 3342 Cov.: 0 AF XY: 0.0968 AC XY: 29364 AN XY: 303344

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.0478

Gnomad4 ASJ exome AF: 0.0403

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.0847

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.0902

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.119 AC: 18167 AN: 152144 Hom.: 1247 Cov.: 32 AF XY: 0.121 AC XY: 9029 AN XY: 74400

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.0601

Gnomad4 ASJ AF: 0.0467

Gnomad4 EAS AF: 0.233

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.0934

Gnomad4 OTH AF: 0.0942

Alfa AF: 0.0972 Hom.: 457

Bravo AF: 0.115

TwinsUK AF: 0.0928 AC: 344

ALSPAC AF: 0.0952 AC: 367

ExAC AF: 0.0880 AC: 1742

Asia WGS AF: 0.153 AC: 530 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2019	This variant is associated with the following publications: (PMID: 30289819) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	2.2
DANN	Benign	0.78
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.83	T
PROVEAN	Benign	0.74	N
REVEL	Benign	0.19
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.038	D
Polyphen		0.037	B
Vest4		0.043
ClinPred		0.0026	T
GERP RS		-0.25

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61747221; hg19: chr12-70037520; COSMIC: COSV58929980;