rs1801466

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1PP2BP4_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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene ABCA4 is included in the ClinGen Criteria Specification Registry.

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:6U:9B:9O:2

Conservation

PhyloP100: 3.42

Publications

144 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
age related macular degeneration 2
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ABCA4 links:

Genome browser will be placed here

ACMG classification

Specifications for ABCA4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -9 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, 8 uncertain in NM_000350.3

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 severe early-childhood-onset retinal dystrophy, retinitis pigmentosa, age related macular degeneration 2, retinitis pigmentosa 19, cone-rod dystrophy 3, ABCA4-related retinopathy, Stargardt disease, cone-rod dystrophy.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000350.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	NM_000350.3	MANE Select	c.5603A>T	p.Asn1868Ile	missense	Exon 40 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.5381A>T	p.Asn1794Ile	missense	Exon 39 of 49	NP_001412253.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.5603A>T	p.Asn1868Ile	missense	Exon 40 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000465352.1	TSL:5	n.19A>T		non_coding_transcript_exon	Exon 1 of 6

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

GnomAD2 exomes

AF:

0.0426

AC:

10696

AN:

251362

AF XY:

0.0430

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 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

African (AFR)

AF:

0.00860

AC:

288

AN:

33474

American (AMR)

AF:

0.0224

AC:

1001

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0319

AC:

835

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0190

AC:

1641

AN:

86258

European-Finnish (FIN)

AF:

0.0402

AC:

2147

AN:

53418

Middle Eastern (MID)

AF:

0.0447

AC:

258

AN:

5766

European-Non Finnish (NFE)

AF:

0.0674

AC:

74936

AN:

1111994

Other (OTH)

AF:

0.0465

AC:

2810

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

5343

10685

16028

21370

26713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2668

5336

8004

10672

13340

<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:

0.0404

AC:

6141

AN:

152110

Hom.:

167

Cov.:

AF XY:

0.0380

AC XY:

2823

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0112

AC:

466

AN:

41504

American (AMR)

AF:

0.0261

AC:

399

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0340

AC:

118

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.0160

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0406

AC:

430

AN:

10588

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0663

AC:

4509

AN:

67980

Other (OTH)

AF:

0.0347

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

316

631

947

1262

1578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0579

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (2)

Severe early-childhood-onset retinal dystrophy (4)

Stargardt disease (2)

ABCA4-related disorder (2)

ABCA4-related retinopathy (1)

Age related macular degeneration 2 (1)

Cone-rod dystrophy 3 (1)

Cone-Rod Dystrophy, Recessive (1)

Macular degeneration (1)

Retinal disorder (1)

Retinal dystrophy (1)

Retinitis pigmentosa (1)

Retinitis Pigmentosa, Recessive (1)

Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Uncertain

0.67

Eigen

Benign

0.026

Eigen_PC

Benign

-0.031

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0069

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.4

PhyloP100

3.4

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.011

Polyphen

0.46

Vest4

0.21

MPC

0.41

ClinPred

0.050

GERP RS

4.8

Varity_R

0.75

gMVP

0.80

Mutation Taster

=42/58

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over