rs1800007

Positions:

• chr11-61951915-T-A
• chr11-61951915-T-C
• chr11-61951915-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_004183.4(BEST1):​c.109T>A​(p.Leu37Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 11/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L37L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BEST1 NM_004183.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.761

Genes affected

BEST1 (HGNC:12703): (bestrophin 1) This gene encodes a member of the bestrophin gene family. This small gene family is characterized by proteins with a highly conserved N-terminus with four to six transmembrane domains. Bestrophins may form chloride ion channels or may regulate voltage-gated L-type calcium-ion channels. Bestrophins are generally believed to form calcium-activated chloride-ion channels in epithelial cells but they have also been shown to be highly permeable to bicarbonate ion transport in retinal tissue. Mutations in this gene are responsible for juvenile-onset vitelliform macular dystrophy (VMD2), also known as Best macular dystrophy, in addition to adult-onset vitelliform macular dystrophy (AVMD) and other retinopathies. Alternative splicing results in multiple variants encoding distinct isoforms.[provided by RefSeq, Nov 2008]

BEST1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity BEST1_HUMAN there are 26 pathogenic changes around while only 0 benign (100%) in NM_004183.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BEST1	NM_004183.4	c.109T>A	p.Leu37Ile	missense_variant	2/11	ENST00000378043.9	NP_004174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BEST1	ENST00000378043.9	c.109T>A	p.Leu37Ile	missense_variant	2/11	1	NM_004183.4	ENSP00000367282.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	6.7
DANN	Benign	0.89
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.19	T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.0	L
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.42
Sift	Benign	0.27	T
Sift4G	Benign	0.41	T
Polyphen		0.031	B
Vest4		0.10
MutPred		0.63		Gain of MoRF binding (P = 0.399);
MVP		0.78
ClinPred		0.21	T
GERP RS		-1.9
Varity_R		0.14

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

LitVar

Other links and lift over

dbSNP: rs1800007; hg19: chr11-61719387;