rs56357060

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 3P and 8B. PM1PP2BP4_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. 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 0.0018 ( 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:11B:1O:2

Conservation

PhyloP100: 0.785

Publications

35 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: Likely_benign. The variant received -5 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 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=0.0137170255).

BS2

High Homozygotes in GnomAdExome4 at 9 AR,AD gene

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.4297G>A	p.Val1433Ile	missense	Exon 29 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.4075G>A	p.Val1359Ile	missense	Exon 28 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.4297G>A	p.Val1433Ile	missense	Exon 29 of 50	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

GnomAD2 exomes

AF:

0.00161

AC:

406

AN:

251484

AF XY:

0.00164

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 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

African (AFR)

AF:

0.000508

AC:

AN:

33480

American (AMR)

AF:

0.00150

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00214

AC:

AN:

39700

South Asian (SAS)

AF:

0.000220

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000580

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00314

AC:

3487

AN:

1112010

Other (OTH)

AF:

0.00195

AC:

118

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

228

456

684

912

1140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

296

444

592

740

<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:

0.00184

AC:

281

AN:

152366

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

125

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000914

AC:

AN:

41590

American (AMR)

AF:

0.00202

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00212

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00276

AC:

188

AN:

68034

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00244

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (11)

Retinal dystrophy (2)

ABCA4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.74

M_CAP

Benign

0.067

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.2

PhyloP100

0.79

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.96

REVEL

Uncertain

0.60

Sift

Uncertain

0.0030

Sift4G

Benign

0.094

Polyphen

0.94

Vest4

0.63

MVP

0.75

MPC

0.070

ClinPred

0.0088

GERP RS

2.3

Varity_R

0.063

gMVP

0.67

Mutation Taster

=87/13

disease causing (ClinVar)

(source)

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

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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