11-61962564-G-A

Variant names:

• chr11-61962564-G-A
• rs149698
• NM_004183.4:c.1410G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004183.4(BEST1):​c.1410G>A​(p.Thr470Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,613,940 control chromosomes in the GnomAD database, including 67,852 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4492 hom., cov: 32)
  • Exomes 𝑓: 0.28 (63360 hom.)
• Consequence: BEST1 NM_004183.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -2.62
• Publications: 19 publications found

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]

FTH1 Gene-Disease associations (from GenCC):

• hemochromatosis type 5

  Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• neurodegeneration with brain iron accumulation 9

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 11-61962564-G-A is Benign according to our data. Variant chr11-61962564-G-A is described in ClinVar as Benign. ClinVar VariationId is 193666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004183.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BEST1	NM_004183.4	MANE Select	c.1410G>A	p.Thr470Thr	synonymous	Exon 10 of 11	NP_004174.1
	BEST1	NM_001440571.1		c.1410G>A	p.Thr470Thr	synonymous	Exon 10 of 10	NP_001427500.1
	BEST1	NM_001440572.1		c.1329G>A	p.Thr443Thr	synonymous	Exon 9 of 9	NP_001427501.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BEST1	ENST00000378043.9	TSL:1 MANE Select	c.1410G>A	p.Thr470Thr	synonymous	Exon 10 of 11	ENSP00000367282.4
	BEST1	ENST00000449131.6	TSL:1	c.1230G>A	p.Thr410Thr	synonymous	Exon 9 of 9	ENSP00000399709.2
	BEST1	ENST00000524877.5	TSL:2	n.5252G>A		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32974 AN: 151982 Hom.: 4490 Cov.: 32

Gnomad AFR AF: 0.0763

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0799

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.255

GnomAD2 exomes AF: 0.226 AC: 56877 AN: 251334 AF XY: 0.228

Gnomad AFR exome AF: 0.0756

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.00191

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.316

Gnomad OTH exome AF: 0.264

GnomAD4 exome AF: 0.282 AC: 412002 AN: 1461840 Hom.: 63360 Cov.: 39 AF XY: 0.276 AC XY: 201037 AN XY: 727216

African (AFR) AF: 0.0692 AC: 2316 AN: 33480

American (AMR) AF: 0.196 AC: 8745 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 7286 AN: 26136

East Asian (EAS) AF: 0.00149 AC: 59 AN: 39670

South Asian (SAS) AF: 0.0944 AC: 8139 AN: 86258

European-Finnish (FIN) AF: 0.286 AC: 15294 AN: 53412

Middle Eastern (MID) AF: 0.287 AC: 1655 AN: 5768

European-Non Finnish (NFE) AF: 0.318 AC: 353225 AN: 1111998

Other (OTH) AF: 0.253 AC: 15283 AN: 60394

GnomAD4 genome AF: 0.217 AC: 32988 AN: 152100 Hom.: 4492 Cov.: 32 AF XY: 0.212 AC XY: 15804 AN XY: 74374

African (AFR) AF: 0.0762 AC: 3164 AN: 41510

American (AMR) AF: 0.252 AC: 3845 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 973 AN: 3470

East Asian (EAS) AF: 0.00348 AC: 18 AN: 5174

South Asian (SAS) AF: 0.0806 AC: 389 AN: 4826

European-Finnish (FIN) AF: 0.278 AC: 2938 AN: 10570

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20712 AN: 67944

Other (OTH) AF: 0.259 AC: 548 AN: 2114

Alfa AF: 0.270 Hom.: 3466

Bravo AF: 0.208

Asia WGS AF: 0.0930 AC: 326 AN: 3478

EpiCase AF: 0.311

EpiControl AF: 0.320

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 09, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Autosomal dominant vitreoretinochoroidopathy Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Vitelliform macular dystrophy 2 Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinitis Pigmentosa, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive bestrophinopathy Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Iron Overload Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinitis pigmentosa 50 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Retinitis pigmentosa Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.61
DANN	Benign	0.90
PhyloP100		-2.6
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs149698; hg19: chr11-61730036; COSMIC: COSV56446580; COSMIC: COSV56446580;