rs1800008

chr11-61962711-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004183.4(BEST1):c.1557C>T(p.Ser519=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,614,032 control chromosomes in the GnomAD database, including 36,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2526 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33535 hom.)
• Consequence: BEST1 NM_004183.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -1.42

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 11-61962711-C-T is Benign according to our data. Variant chr11-61962711-C-T is described in ClinVar as [Benign]. Clinvar id is 99680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61962711-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BEST1	NM_004183.4	c.1557C>T	p.Ser519=	synonymous_variant	10/11	ENST00000378043.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BEST1	ENST00000378043.9	c.1557C>T	p.Ser519=	synonymous_variant	10/11	1	NM_004183.4	P1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24202 AN: 152090 Hom.: 2530 Cov.: 32

Gnomad AFR AF: 0.0453

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.175 AC: 43944 AN: 251328 Hom.: 4681 AF XY: 0.185 AC XY: 25132 AN XY: 135828

Gnomad AFR exome AF: 0.0431

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.206

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.206 AC: 301232 AN: 1461824 Hom.: 33535 Cov.: 38 AF XY: 0.208 AC XY: 151502 AN XY: 727200

Gnomad4 AFR exome AF: 0.0404

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.304

Gnomad4 EAS exome AF: 0.00116

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.195

GnomAD4 genome AF: 0.159 AC: 24195 AN: 152208 Hom.: 2526 Cov.: 32 AF XY: 0.157 AC XY: 11707 AN XY: 74418

Gnomad4 AFR AF: 0.0453

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.00328

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.163

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.184

Alfa AF: 0.207 Hom.: 2022

Bravo AF: 0.152

Asia WGS AF: 0.0820 AC: 288 AN: 3478

EpiCase AF: 0.237

EpiControl AF: 0.236

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 16, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -

Retinitis Pigmentosa, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal dominant vitreoretinochoroidopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Vitelliform macular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Iron Overload Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.32
Dann	Benign	0.60

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

LitVar

Other links and lift over

dbSNP: rs1800008; hg19: chr11-61730183; COSMIC: COSV56444774; COSMIC: COSV56444774;