12-69678699-C-G

Variant names:

• chr12-69678699-C-G
• rs3741755
• NM_032735.3:c.636+40G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032735.3(BEST3):​c.636+40G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,595,536 control chromosomes in the GnomAD database, including 123,597 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.35 (9491 hom., cov: 31)
  • Exomes 𝑓: 0.39 (114106 hom.)
• Consequence: BEST3 NM_032735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.321
• Publications: 9 publications found

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]

ENSG00000305711 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEST3	NM_032735.3	c.636+40G>C		intron_variant	Intron 5 of 9	ENST00000330891.10	NP_116124.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BEST3	ENST00000330891.10	c.636+40G>C		intron_variant	Intron 5 of 9	5	NM_032735.3	ENSP00000332413.5

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52588 AN: 151892 Hom.: 9485 Cov.: 31

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.356

GnomAD2 exomes AF: 0.390 AC: 96059 AN: 246170 AF XY: 0.405

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.327

Gnomad ASJ exome AF: 0.430

Gnomad EAS exome AF: 0.280

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.392

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.392 AC: 566220 AN: 1443526 Hom.: 114106 Cov.: 26 AF XY: 0.399 AC XY: 286587 AN XY: 719038

African (AFR) AF: 0.257 AC: 8486 AN: 33058

American (AMR) AF: 0.327 AC: 14560 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 11127 AN: 25914

East Asian (EAS) AF: 0.231 AC: 9124 AN: 39516

South Asian (SAS) AF: 0.566 AC: 48340 AN: 85448

European-Finnish (FIN) AF: 0.401 AC: 21204 AN: 52838

Middle Eastern (MID) AF: 0.487 AC: 2790 AN: 5730

European-Non Finnish (NFE) AF: 0.389 AC: 427170 AN: 1096820

Other (OTH) AF: 0.392 AC: 23419 AN: 59728

GnomAD4 genome AF: 0.346 AC: 52623 AN: 152010 Hom.: 9491 Cov.: 31 AF XY: 0.349 AC XY: 25930 AN XY: 74284

African (AFR) AF: 0.251 AC: 10424 AN: 41476

American (AMR) AF: 0.315 AC: 4815 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 1482 AN: 3472

East Asian (EAS) AF: 0.260 AC: 1346 AN: 5176

South Asian (SAS) AF: 0.539 AC: 2597 AN: 4816

European-Finnish (FIN) AF: 0.412 AC: 4347 AN: 10542

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.389 AC: 26403 AN: 67958

Other (OTH) AF: 0.353 AC: 742 AN: 2104

Alfa AF: 0.369 Hom.: 1953

Bravo AF: 0.333

Asia WGS AF: 0.373 AC: 1297 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.52
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3741755; hg19: chr12-70072479; COSMIC: COSV56994097; COSMIC: COSV56994097;