1-94010911-T-A

Position:

chr1-94010911-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBA1

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. 12/20 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:5B:8O:2

Conservation

PhyloP100: 3.42

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 Benign. Variant got -10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.5603A>T	p.Asn1868Ile	missense_variant	40/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.5381A>T	p.Asn1794Ile	missense_variant	39/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.5603A>T	p.Asn1868Ile	missense_variant	40/50	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000465352.1 linkuse as main transcript	n.19A>T		non_coding_transcript_exon_variant	1/6	5

Frequencies

GnomAD3 genomes

AF:

0.0404

AC:

6143

AN:

151992

Hom.:

167

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0565

AC XY:

41063

AN XY:

727226

show subpopulations

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.:

AF XY:

0.0380

AC XY:

2823

AN XY:

74364

show subpopulations

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:

ESP6500EA

AF:

0.0665

AC:

572

ExAC

AF:

0.0445

AC:

5408

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0647

EpiControl

AF:

0.0663

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy

Pathogenic:2Uncertain:1Other:1

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
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -

not provided

Uncertain:1Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2021	- -
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	- -
not provided, no classification provided	literature only	Retina International	-	- -

ABCA4-related disorder

Pathogenic:1Benign: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. -
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. -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

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

- -

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

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Uncertain

0.67

D;D

Eigen

Benign

0.026

Eigen_PC

Benign

-0.031

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0069

T;T

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.4

.;M

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-4.9

.;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.46

.;P

Vest4

0.21

MPC

0.41

ClinPred

0.050

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

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