11-61959912-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_004183.4(BEST1):c.969T>A(p.Asp323Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D323V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: BEST1 NM_004183.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.682

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]

FTH1 (HGNC:3976): (ferritin heavy chain 1) This gene encodes the heavy subunit of ferritin, the major intracellular iron storage protein in prokaryotes and eukaryotes. It is composed of 24 subunits of the heavy and light ferritin chains. Variation in ferritin subunit composition may affect the rates of iron uptake and release in different tissues. A major function of ferritin is the storage of iron in a soluble and nontoxic state. Defects in ferritin proteins are associated with several neurodegenerative diseases. This gene has multiple pseudogenes. Several alternatively spliced transcript variants have been observed, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

LOC107984334 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_004183.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BEST1	NM_004183.4	c.969T>A	p.Asp323Glu	missense_variant	9/11	ENST00000378043.9
LOC107984334	XR_001748245.2			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BEST1	ENST00000378043.9	c.969T>A	p.Asp323Glu	missense_variant	9/11	1	NM_004183.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460192 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726370

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vitelliform macular dystrophy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 05, 2019

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Benign	13
Dann	Benign	0.93
DEOGEN2	Uncertain	0.70	D;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.42	N
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.4	M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;N;D;N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.92		Loss of sheet (P = 0.0817);.;
MVP		0.95
MPC		0.96
ClinPred		0.91	D
GERP RS		-3.4
Varity_R		0.86
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1941875734; hg19: chr11-61727384;