NM_004183.4:c.219C>A

Variant names:

• chr11-61955173-C-A
• rs1109748
• NM_004183.4:c.219C>A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The NM_004183.4(BEST1):​c.219C>A​(p.Ile73Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,614,080 control chromosomes in the GnomAD database, including 31,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2617 hom., cov: 32)
  • Exomes 𝑓: 0.13 (29049 hom.)
• Consequence: BEST1 NM_004183.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: -0.434

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]

LOC107984334 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.13).
• BP6: Variant 11-61955173-C-A is Benign according to our data. Variant chr11-61955173-C-A is described in ClinVar as [Benign]. Clinvar id is 99693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61955173-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEST1	NM_004183.4	c.219C>A	p.Ile73Ile	synonymous_variant	Exon 3 of 11	ENST00000378043.9	NP_004174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BEST1	ENST00000378043.9	c.219C>A	p.Ile73Ile	synonymous_variant	Exon 3 of 11	1	NM_004183.4	ENSP00000367282.4

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18910 AN: 152104 Hom.: 2616 Cov.: 32

Gnomad AFR AF: 0.0878

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.531

Gnomad FIN AF: 0.0692

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0743

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.205 AC: 51573 AN: 251400 Hom.: 10675 AF XY: 0.213 AC XY: 28881 AN XY: 135890

Gnomad AFR exome AF: 0.0847

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.0405

Gnomad EAS exome AF: 0.680

Gnomad SAS exome AF: 0.515

Gnomad FIN exome AF: 0.0699

Gnomad NFE exome AF: 0.0767

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.126 AC: 184849 AN: 1461858 Hom.: 29049 Cov.: 65 AF XY: 0.137 AC XY: 99437 AN XY: 727234

Gnomad4 AFR exome AF: 0.0831

Gnomad4 AMR exome AF: 0.288

Gnomad4 ASJ exome AF: 0.0417

Gnomad4 EAS exome AF: 0.749

Gnomad4 SAS exome AF: 0.504

Gnomad4 FIN exome AF: 0.0677

Gnomad4 NFE exome AF: 0.0737

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.124 AC: 18915 AN: 152222 Hom.: 2617 Cov.: 32 AF XY: 0.136 AC XY: 10101 AN XY: 74432

Gnomad4 AFR AF: 0.0877

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.0432

Gnomad4 EAS AF: 0.678

Gnomad4 SAS AF: 0.530

Gnomad4 FIN AF: 0.0692

Gnomad4 NFE AF: 0.0743

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0927 Hom.: 2871

Bravo AF: 0.131

Asia WGS AF: 0.530 AC: 1839 AN: 3478

EpiCase AF: 0.0724

EpiControl AF: 0.0742

ClinVar

Significance: Benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4 Other:1

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Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

This variant is associated with the following publications: (PMID: 32207364) -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:4

Apr 15, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Vitelliform macular dystrophy 2 Benign:2

Jan 12, 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. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant vitreoretinochoroidopathy Benign:1

Jan 12, 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. -

Vitelliform macular dystrophy 2;C2750789:Retinitis pigmentosa 50;C3888099:Autosomal dominant vitreoretinochoroidopathy;C3888198:Autosomal recessive bestrophinopathy Benign:1

Jan 27, 2022

Fulgent Genetics, Fulgent Genetics

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 12, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.13
CADD	Benign	13
DANN	Benign	0.87

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: rs1109748; hg19: chr11-61722645;