rs145525174

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM1PP2BP4_StrongBP6_Very_StrongBS2

The NM_000350.3(ABCA4):c.1654G>A(p.Val552Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,614,084 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V552A) has been classified as Uncertain significance. The gene ABCA4 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 16 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: 2.49

Publications

26 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 -13 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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=0.013788432).

BP6

Variant 1-94063218-C-T is Benign according to our data. Variant chr1-94063218-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 16 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.1654G>A	p.Val552Ile	missense	Exon 12 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.1654G>A	p.Val552Ile	missense	Exon 12 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.1654G>A	p.Val552Ile	missense	Exon 12 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000649773.1		c.1654G>A	p.Val552Ile	missense	Exon 12 of 19	ENSP00000496882.1	A0A3B3IRV8

Frequencies

GnomAD3 genomes

AF:

0.00239

AC:

364

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00432

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00269

AC:

677

AN:

251436

AF XY:

0.00273

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.00463

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00385

AC:

5622

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

2783

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33480

American (AMR)

AF:

0.000537

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00216

AC:

186

AN:

86258

European-Finnish (FIN)

AF:

0.00243

AC:

130

AN:

53420

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00460

AC:

5115

AN:

1111964

Other (OTH)

AF:

0.00230

AC:

139

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

351

702

1054

1405

1756

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

376

564

752

940

<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:

0.00239

AC:

364

AN:

152244

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

161

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41546

American (AMR)

AF:

0.000588

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00187

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00189

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00432

AC:

294

AN:

68020

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00361

Hom.:

Bravo

AF:

0.00227

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00264

AC:

320

Asia WGS

AF:

0.00144

AC:

AN:

3476

EpiCase

AF:

0.00376

EpiControl

AF:

0.00338

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Retinal dystrophy (2)

ABCA4-related disorder (1)

Cone-Rod Dystrophy, Recessive (1)

Macular degeneration (1)

not specified (1)

Retinitis Pigmentosa, Recessive (1)

Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.093

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

1.2

PhyloP100

2.5

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.75

REVEL

Pathogenic

0.69

Sift

Benign

0.24

Sift4G

Benign

0.24

Polyphen

0.045

Vest4

0.28

MVP

0.78

MPC

0.16

ClinPred

0.034

GERP RS

4.0

Varity_R

0.063

gMVP

0.73

Mutation Taster

=68/32

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over