rs6666652

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000350.3(ABCA4):c.6764G>T(p.Ser2255Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0619 in 1,613,784 control chromosomes in the GnomAD database, including 10,691 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 4974 hom., cov: 33)

Exomes 𝑓: 0.051 ( 5717 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 0.742

Publications

41 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
severe early-childhood-onset retinal dystrophy
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
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

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 cone-rod dystrophy 3, retinitis pigmentosa 19, ABCA4-related retinopathy, severe early-childhood-onset retinal dystrophy, cone-rod dystrophy, Stargardt disease, retinitis pigmentosa.

BP4

Computational evidence support a benign effect (MetaRNN=1.2466311E-4).

BP6

Variant 1-93996161-C-A is Benign according to our data. Variant chr1-93996161-C-A is described in ClinVar as Benign. ClinVar VariationId is 99494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 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.6764G>T	p.Ser2255Ile	missense	Exon 49 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.6542G>T	p.Ser2181Ile	missense	Exon 48 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.6764G>T	p.Ser2255Ile	missense	Exon 49 of 50	ENSP00000359245.3	P78363

Frequencies

GnomAD3 genomes

AF:

0.165

AC:

25160

AN:

152116

Hom.:

4967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.480

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.0925

Gnomad ASJ

AF:

0.0616

Gnomad EAS

AF:

0.0227

Gnomad SAS

AF:

0.0553

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.134

Gnomad NFE

AF:

0.0411

Gnomad OTH

AF:

0.146

GnomAD2 exomes

AF:

0.0715

AC:

17958

AN:

251210

AF XY:

0.0630

show subpopulations

Gnomad AFR exome

AF:

0.494

Gnomad AMR exome

AF:

0.0617

Gnomad ASJ exome

AF:

0.0682

Gnomad EAS exome

AF:

0.0270

Gnomad FIN exome

AF:

0.00578

Gnomad NFE exome

AF:

0.0400

Gnomad OTH exome

AF:

0.0660

GnomAD4 exome

AF:

0.0511

AC:

74676

AN:

1461550

Hom.:

5717

Cov.:

AF XY:

0.0499

AC XY:

36308

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.499

AC:

16711

AN:

33460

American (AMR)

AF:

0.0657

AC:

2938

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0702

AC:

1836

AN:

26136

East Asian (EAS)

AF:

0.0230

AC:

912

AN:

39700

South Asian (SAS)

AF:

0.0506

AC:

4367

AN:

86256

European-Finnish (FIN)

AF:

0.00682

AC:

363

AN:

53252

Middle Eastern (MID)

AF:

0.126

AC:

725

AN:

5766

European-Non Finnish (NFE)

AF:

0.0381

AC:

42391

AN:

1111882

Other (OTH)

AF:

0.0734

AC:

4433

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

3506

7011

10517

14022

17528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1840

3680

5520

7360

9200

<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:

0.166

AC:

25199

AN:

152234

Hom.:

4974

Cov.:

AF XY:

0.160

AC XY:

11934

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.480

AC:

19914

AN:

41482

American (AMR)

AF:

0.0922

AC:

1411

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0616

AC:

214

AN:

3472

East Asian (EAS)

AF:

0.0226

AC:

117

AN:

5180

South Asian (SAS)

AF:

0.0541

AC:

261

AN:

4822

European-Finnish (FIN)

AF:

0.00518

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.144

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0411

AC:

2793

AN:

68030

Other (OTH)

AF:

0.145

AC:

306

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

806

1612

2419

3225

4031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

224

448

672

896

1120

<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:

0.0760

Hom.:

6658

Bravo

AF:

0.186

TwinsUK

AF:

0.0361

AC:

134

ALSPAC

AF:

0.0376

AC:

145

ESP6500AA

AF:

0.478

AC:

2105

ESP6500EA

AF:

0.0465

AC:

400

ExAC

AF:

0.0802

AC:

9739

Asia WGS

AF:

0.0660

AC:

231

AN:

3478

EpiCase

AF:

0.0498

EpiControl

AF:

0.0510

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

ABCA4-related disorder (1)

Cone-Rod Dystrophy, Recessive (1)

Macular degeneration (1)

Retinal dystrophy (1)

Retinitis Pigmentosa, Recessive (1)

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 (1)

Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

1.7

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.26

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.048

MetaRNN

Benign

0.00012

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.34

PhyloP100

0.74

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.99

REVEL

Benign

0.20

Sift

Benign

0.13

Sift4G

Benign

0.089

Polyphen

0.0

Vest4

0.026

MPC

0.099

ClinPred

0.0043

GERP RS

-2.0

Varity_R

0.085

gMVP

0.22

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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