rs28938473

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 6P and 9B. PM1PM5PP2PP3BP4_StrongBP6BS2

The NM_000350.3(ABCA4):c.5908C>T(p.Leu1970Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00479 in 1,613,956 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1970H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0035 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 24 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6B:4O:1

Conservation

PhyloP100: 6.77

Publications

29 publications found

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 Gene-Disease associations (from GenCC):

ABCA4-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
cone-rod dystrophy 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
severe early-childhood-onset retinal dystrophy
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
retinitis pigmentosa 19
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Stargardt disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94007730-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3672358.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 578 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: -0.65813 (below the threshold of 3.09). Trascript score misZ: 1.3628 (below the threshold of 3.09). GenCC associations: The gene is linked to cone-rod dystrophy 3, retinitis pigmentosa 19, ABCA4-related retinopathy, severe early-childhood-onset retinal dystrophy, cone-rod dystrophy, Stargardt disease, retinitis pigmentosa.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, PrimateAI, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0254018).

BP6

Variant 1-94007731-G-A is Benign according to our data. Variant chr1-94007731-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7892.

BS2

High Homozygotes in GnomAdExome4 at 24 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.5908C>T	p.Leu1970Phe	missense_variant	Exon 43 of 50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.5686C>T	p.Leu1896Phe	missense_variant	Exon 42 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCA4	ENST00000370225.4 link	c.5908C>T	p.Leu1970Phe	missense_variant	Exon 43 of 50	1	NM_000350.3	ENSP00000359245.3	P78363
ABCA4	ENST00000465352.1 link	n.324C>T		non_coding_transcript_exon_variant	Exon 4 of 6	5
ABCA4	ENST00000484388.1 link	n.22C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00354

AC:

538

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00491

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00300

AC:

751

AN:

250638

AF XY:

0.00308

show subpopulations

Gnomad AFR exome

AF:

0.00143

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00464

Gnomad OTH exome

AF:

0.00490

GnomAD4 exome

AF:

0.00492

AC:

7186

AN:

1461696

Hom.:

Cov.:

AF XY:

0.00474

AC XY:

3443

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33478

American (AMR)

AF:

0.00273

AC:

122

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00163

AC:

141

AN:

86258

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

53306

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00586

AC:

6519

AN:

1111934

Other (OTH)

AF:

0.00467

AC:

282

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

349

699

1048

1398

1747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

268

536

804

1072

1340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00353

AC:

538

AN:

152260

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00169

AC:

AN:

41532

American (AMR)

AF:

0.00660

AC:

101

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00146

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00491

AC:

334

AN:

68026

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00410

Hom.:

Bravo

AF:

0.00388

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00290

AC:

352

EpiCase

AF:

0.00496

EpiControl

AF:

0.00486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3Other:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCA4: PM5:Supporting, PP3, BS2 -

Jan 07, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jul 07, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 9781034, 25087612, 9295268, 23953153, 9973280, 10958763, 12515255, 22264887, 28118664, 27408750, 28157192, 29925512, 30718709, 33633436) -

Severe early-childhood-onset retinal dystrophy

Uncertain:2

Sep 25, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Aug 27, 2021

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:2

Jan 01, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 30, 2018

Blueprint Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Vitreoretinopathy

Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Stargardt disease

Pathogenic:1

May 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

ABCA4-related disorder

Uncertain:1

Aug 27, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ABCA4 c.5908C>T variant is predicted to result in the amino acid substitution p.Leu1970Phe. This variant has been reported many times in individuals with Stargardt disease, late-onset fundus flavimaculatus, and/or age-related macular degeneration (Lewis et al. 1999. PubMed ID: 9973280; Allikmets et al. 1997. PubMed ID: 9295268; Rozet et al. 1998. PubMed ID: 9781034; Webster et al. 2001. PubMed ID: 11328725; Thiadens et al. 2012. PubMed ID: 22264887; Fujinami et al. 2019. PubMed ID: 29925512). However, in some of these cases a second causative variant in ABCA4 was not detected. Additionally, this variant has been reported in individuals in which there were pathogenic variants in different genes that could explain their inherited retinal dystrophy (Jespersgaard et al. 2019. PubMed ID: 30718709; Zhu et al. 2022. PubMed ID: 35456422). Here, at PreventionGenetics, we have also detected this variant in the absence of a second causative variant, and sometimes these individuals were positive for pathogenic variants in different genes (Internal Data). This variant is documented in 0.46% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including three homozygotes (http://gnomad.broadinstitute.org/variant/1-94473287-G-A). Given the conflicting evidence, the clinical significance of this variant is uncertain at this time. -

not specified

Benign:1

Jun 22, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

D;D

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.025

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.9

.;M

PhyloP100

6.8

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.7

.;D

REVEL

Pathogenic

0.89

Sift

Benign

0.068

.;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.96

MVP

0.94

MPC

0.48

ClinPred

0.0086

GERP RS

5.1

Varity_R

0.61

gMVP

0.94

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over