rs56357060

Positions:

chr1-94030483-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_000350.3(ABCA4):c.4297G>A(p.Val1433Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,614,254 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 9 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:1O:2

Conservation

PhyloP100: 0.785

Variant links:

Genes affected

ABCA4 (HGNC:34): (ATP binding cassette subfamily A member 4) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is a retina-specific ABC transporter with N-retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essental molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile-onset macular degeneration. Mutations in this gene are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. [provided by RefSeq, Sep 2019]

ABCA4 links:

ABCA4 (HGNC:):

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 uncertain in NM_000350.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0137170255).

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.4297G>A	p.Val1433Ile	missense_variant	29/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.4075G>A	p.Val1359Ile	missense_variant	28/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.4297G>A	p.Val1433Ile	missense_variant	29/50	1	NM_000350.3	ENSP00000359245.3		P78363

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

281

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000916

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00276

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00161

AC:

406

AN:

251484

Hom.:

AF XY:

0.00164

AC XY:

223

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00185

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00240

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00262

AC:

3827

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00256

AC XY:

1864

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00150

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00214

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.000580

Gnomad4 NFE exome

AF:

0.00314

Gnomad4 OTH exome

AF:

0.00195

GnomAD4 genome

AF:

0.00184

AC:

281

AN:

152366

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

125

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00202

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00212

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00276

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00256

Hom.:

Bravo

AF:

0.00177

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00143

AC:

173

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:8Benign:1Other:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ABCA4 p.Val1433Ile variant was identified in 9 of 1492 proband chromosomes (frequency: 0.006) from individuals or families with stargardt disease, cone-rod dystrophy, age-related macular degeneration and retinitis pigmentosa (Schulz_2017_PMID:28118664; Thiadens_2012_PMID:22264887; Aguirre-Lamban_2009_PMID:19028736; Baum_2003_PMID:12592048; Lewis_1999_PMID:9973280). The variant was identified in dbSNP (ID: rs56357060), ClinVar (classified as likely pathogenic by Institute of Human Genetics, Univ. Regensburg and as a VUS by EGL Genetic Diagnostics and Illumina) and in LOVD 3.0 (classified as pathogenic once, a VUS four times and likely benign twice). The variant was also identified in control databases in 470 of 282886 chromosomes (1 homozygous) at a frequency of 0.001661 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 322 of 129192 chromosomes (freq: 0.002492), Other in 14 of 7226 chromosomes (freq: 0.001937), East Asian in 35 of 19952 chromosomes (freq: 0.001754), Latino in 56 of 35440 chromosomes (freq: 0.00158), European (Finnish) in 19 of 25118 chromosomes (freq: 0.000756), African in 16 of 24972 chromosomes (freq: 0.000641), South Asian in 7 of 30616 chromosomes (freq: 0.000229), and Ashkenazi Jewish in 1 of 10370 chromosomes (freq: 0.000096). The p.Val1433 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 15, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ABCA4: PM1 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2019	The ABCA4 variant c.4297G>A; p.Val1433Ile (rs56357060) is reported in the medical literature in individuals with ABCA4-related disease as well as age related macular degeneration in the compound heterozygous state in a few individuals, but often without an additional pathogenic variant (Aguirre-Lamban 2009, Klevering 2004, Lewis 1999, Michaelides 2007, Song 2011, Souied 2000, Taylor 2017, Thiadens 2012, Webster 2001). The variant is reported in the ClinVar database (Variation ID: 99274) and in the Genome Aggregation Database in the general population with an allele frequency of 0.2% (470/282886 alleles including 1 homozygote). The amino acid at this position is highly conserved but computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty. References: Aguirre-Lamban J et al. Molecular analysis of the ABCA4 gene for reliable detection of allelic variations in Spanish patients: identification of 21 novel variants. Br J Ophthalmol. 2009 May;93(5):614-21. Klevering BJ et al. Three families displaying the combination of Stargardt's disease with cone-rod dystrophy or retinitis pigmentosa. Ophthalmology. 2004 Mar;111(3):546-53. Lewis RA et al. Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am J Hum Genet. 1999 Feb;64(2):422-34. Michaelides M et al. ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy. Br J Ophthalmol. 2007 Dec;91(12):1650-5. Song J et al. High-throughput retina-array for screening 93 genes involved in inherited retinal dystrophy. Invest Ophthalmol Vis Sci. 2011 Nov 25;52(12):9053-60. Souied EH et al. ABCR gene analysis in familial exudative age-related macular degeneration. Invest Ophthalmol Vis Sci. 2000 Jan;41(1):244-7. Taylor RL et al. Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease. Ophthalmology. 2017 Jul;124(7):985-991. Thiadens AA et al. Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. Ophthalmology. 2012 Apr;119(4):819-26 Webster AR et al. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2022	Observed in patients with Stargardt disease in published literature who were reported to have V1433I on the same allele (in cis) with other ABCA4 variants or seen phase unknown with two other pathogenic ABCA4 variants, therefore questioning the pathogenicity of V1433I (Klevering et al., 2004; Lambertus et al., 2016; Murro et al., 2017; Birtel et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22995991, 34073554, 22025579, 27527345, 28002570, 28430335, 34426522, 20981092, 35119454, 29555955, 33090715, 15494742, 28341476, 32037395, 24409374, 22264887, 9973280) -

ABCA4-related disorder

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The ABCA4 c.4297G>A (p.Val1433Ile) missense variant has been reported in 14 studies in individuals with a range of ocular disorders (Lewis et al. 1999; Souied et al. 2000; Webster et al. 2001; Baum et al. 2003; Klevering et al. 2004; Valverde et al. 2007; Michaelides et al. 2007; Aguirre-Lamban et al. 2009; Kellner et al. 2009; Passerini et al. 2010; Song et al. 2011; Verdina et al. 2012; Huang et al. 2014; Grassmann et al. 2015). The p.Val1433Ile variant was found in a homozygous state in two individuals with Stargardt disease (STGD), in a compound heterozygous state in one individual with STGD and one with retinal degeneration. The variant was further reported in a complex compound heterozygous state in a patient with recessive cone-rod dystrophy (CRD), and in a heterozygous state in four patients with recessive CRD, three patients with age-related macular degeneration (AMD), and one patient each with STGD and bullâ€™s eye maculopathy. Segregation analysis in one AMD family revealed that the variant did not segregate with disease. The variant was found in a heterozygous state in two of 484 controls and is reported at a frequency of 0.00441 in the Other population of the Exome Aggregation Consortium. Additionally, one homozygote is reported in the European (non-Finnish) population of the Exome Aggregation Consortium. Despite the evidence of causality, the discordant reports of lack of co-segregation of the variant with disease and the presence of an ostensibly healthy homozygote in the frequency databases present conflicting support for pathogenicity. The p.Val1433Ile variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 11, 2024	The ABCA4 c.4297G>A variant is predicted to result in the amino acid substitution p.Val1433Ile. This variant has been reported in the heterozygous state alone or with a second ABCA4 variant in individuals with Stargardt disease and cone-rod dystrophy (for example, see Lewis et al. 1999. PubMed: 9973280; Thiadens et al. 2012. PubMed: 22264887; Taylor et al. 2017. PubMed ID: 28341476; Del Pozo-Valero et al. 2022. PubMed ID: 35119454). Of note, this variant has also been detected in an individual who also had a potential causative variant in the PROM1 gene (associated with a retinal disorder) (Song et al. 2011. PubMed: 22025579). However, this variant is reported in 0.25% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including in several homozygous individuals in the latest gnomAD dataset (https://gnomad.broadinstitute.org/variant/1-94030483-C-T?dataset=gnomad_r4), which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Retinal dystrophy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -
Uncertain significance, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.067

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.2

.;M

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.96

N;N

REVEL

Uncertain

0.60

Sift

Uncertain

0.0030

D;T

Sift4G

Benign

0.094

T;T

Polyphen

0.94

.;P

Vest4

0.63

MVP

0.75

MPC

0.070

ClinPred

0.0088

GERP RS

2.3

Varity_R

0.063

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over