rs1801466

chr1-94010911-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP4_Strong BA1

The NM_000350.3(ABCA4):c.5603A>T(p.Asn1868Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0558 in 1,613,960 control chromosomes in the GnomAD database, including 2,989 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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 0.040 (167 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2822 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:4 B:8 O:2
• Conservation: PhyloP100: 3.42

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000350.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0069182813).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.5603A>T	p.Asn1868Ile	missense_variant	40/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.5381A>T	p.Asn1794Ile	missense_variant	39/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.5603A>T	p.Asn1868Ile	missense_variant	40/50	1	NM_000350.3	P1
ABCA4	ENST00000465352.1	n.19A>T		non_coding_transcript_exon_variant	1/6	5

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6143 AN: 151992 Hom.: 167 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0350

GnomAD3 exomes AF: 0.0426 AC: 10696 AN: 251362 Hom.: 328 AF XY: 0.0430 AC XY: 5848 AN XY: 135844

Gnomad AFR exome AF: 0.00990

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0182

Gnomad FIN exome AF: 0.0394

Gnomad NFE exome AF: 0.0674

Gnomad OTH exome AF: 0.0527

GnomAD4 exome AF: 0.0574 AC: 83918 AN: 1461850 Hom.: 2822 Cov.: 36 AF XY: 0.0565 AC XY: 41063 AN XY: 727226

Gnomad4 AFR exome AF: 0.00860

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.0319

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0190

Gnomad4 FIN exome AF: 0.0402

Gnomad4 NFE exome AF: 0.0674

Gnomad4 OTH exome AF: 0.0465

GnomAD4 genome AF: 0.0404 AC: 6141 AN: 152110 Hom.: 167 Cov.: 32 AF XY: 0.0380 AC XY: 2823 AN XY: 74364

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.0261

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.0663

Gnomad4 OTH AF: 0.0347

Alfa AF: 0.0579 Hom.: 219

Bravo AF: 0.0380

TwinsUK AF: 0.0631 AC: 234

ALSPAC AF: 0.0633 AC: 244

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.0665 AC: 572

ExAC AF: 0.0445 AC: 5408

Asia WGS AF: 0.00808 AC: 29 AN: 3478

EpiCase AF: 0.0647

EpiControl AF: 0.0663

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:4 Benign:8 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy Pathogenic:2 Uncertain:1 Other:1

Established risk allele, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 23, 2022	This variant was identified as compound heterozygous with NM_000350.3:c.67-2A>G -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
other, no assertion criteria provided	clinical testing	Molecular Vision Laboratory	Sep 10, 2018	Asn1868Ile has been found to be associated with autosomal recessive Stargardt disease (STGD1). Its presence explained >40% of monoallelic ABCA4 carriers in two separate STGD1 cohorts. Penetrance was estimated to be less than 5% based on expected incidence of Asn1868Ile combinations with severe ABCA4 mutations and estimated prevalence of cases due to these combinations in a STGD1 cohort. hypomorphic allele
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -

not provided Uncertain:1 Benign:2 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2019	The variant in the ABCA4 gene that is indicated below was identified in this patient and is not currently known to cause an ABCA4-related disorder. The variant is observed in 8,580/129,074 (6.65%) alleles from individuals of non-Finnish European background and in 11,928/282,712 (4.22%) global alleles, including 364 homozygous individuals, in large population cohorts (Lek et al., 2016). However, some publications theorize N1868I may cause hypomorphic retinal dystrophy only when in trans with a pathogenic ABCA4 variant (Zernant et al., 2017; Runhart et al., 2018). Individuals who had the N1868I variant in trans with another ABCA4 pathogenic variant were reported to have late-onset Stargardt disease (Zernant et al., 2017; Runhart et al,. 2018).; This variant is associated with the following publications: (PMID: 26780318, 21330655, 32845050, 28118664, 11328725, 28446513, 27775217, 24265693, 11017087, 29555955, 29971439, 23443024, 30204727, 30480703, 30480704, 29925512, 30670881, 30643219, 31618761, 31456290, 32467599, 32037395) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2021	- -

ABCA4-related condition Pathogenic:1

Established risk allele, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2024

This variant is reported with a global allele frequency of 4.2% in gnomAD, with the highest population frequency being 6.6% in individuals of European (Non-Finnish) descent, including hundreds of homozygous individuals. Allele frequencies this high are most often associated with variants that are considered benign for Mendelian disease. However, statistical analyses have shown that this variant is significantly enriched in Stargardt patient populations compared to controls (Webster et al. 2001. PubMed ID: 11328725; Aguirre-Lamban et al. 2011. PubMed ID: 21330655). Large cohort studies of individuals with only one known pathogenic variant in ABCA4 found that this c.5603A>T (p.Asn1868Ile) variant could explain ~50% of those missing heritability cases (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Despite the enrichment in the patient population, the very high allele frequency has been used to estimate that the penetrance of this variant is less than 5% (Runhart et al. 2018. PubMed ID: 29971439). Additionally, it has been demonstrated that patients who harbor this variant have a more mild phenotype and an average age of onset in the 4th decade compared to the typical juvenile-onset associated with ABCA4 disease (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Functional studies have shown that this variant causes a small but significant decrease in the ATPase activity (Sun et al. 2000. PubMed ID: 11017087) and a decrease in substrate binding ability (Garces et al. 2021. PubMed ID: 33375396). This variant has often been found in cis with other ABCA4 variants such as c.2588G>C, c.5461-10T>C, and many others; forming a complex allele which can modify the penetrance and severity of disease (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Given all the evidence, we interpret c.5603A>T (p.Asn1868Ile) as a risk variant for mild and late-onset disease when in trans with a severe variant. -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Apr 01, 2021

The p.Asn1868Ile variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM3, PM3, BP2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Stargardt disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Age related macular degeneration 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 27, 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: PP2,PP3,BS1. -

Cone-rod dystrophy 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

This variant was identified as compound heterozygous. -

Retinitis Pigmentosa, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 20, 2014

- -

Stargardt Disease, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

ABCA4-Related Disorders Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cone-Rod Dystrophy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Macular degeneration Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	21
Dann	Benign	0.92
DEOGEN2	Uncertain	0.67	D;D
Eigen	Benign	0.026
Eigen_PC	Benign	-0.031
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0069	T;T
MetaSVM	Uncertain	0.66	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.32	T
REVEL	Uncertain	0.40
Sift4G	Uncertain	0.011	D;D
Polyphen		0.46	.;P
Vest4		0.21
MPC		0.41
ClinPred		0.050	T
GERP RS		4.8
Varity_R		0.75
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1801466; hg19: chr1-94476467;