1-94098927-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 5P and 13B. PM1PM5PP2BP4_StrongBP6BA1

The NM_000350.3(ABCA4):c.635G>A(p.Arg212His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,613,470 control chromosomes in the GnomAD database, including 1,401 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. R212C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.049 ( 184 hom., cov: 33)

Exomes 𝑓: 0.039 ( 1217 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13O:1

Conservation

PhyloP100: 3.20

Publications

36 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: Benign. The variant received -8 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94098928-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 7898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.017632037).

BP6

Variant 1-94098927-C-T is Benign according to our data. Variant chr1-94098927-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 99454.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.635G>A	p.Arg212His	missense_variant	Exon 6 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1 link	c.635G>A	p.Arg212His	missense_variant	Exon 6 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 link	c.635G>A	p.Arg212His	missense_variant	Exon 6 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1 link	c.635G>A	p.Arg212His	missense_variant	Exon 6 of 19			ENSP00000496882.1

Frequencies

GnomAD3 genomes

AF:

0.0486

AC:

7389

AN:

152150

Hom.:

183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0682

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0477

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.0581

Gnomad SAS

AF:

0.0292

Gnomad FIN

AF:

0.0544

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0379

Gnomad OTH

AF:

0.0397

GnomAD2 exomes

AF:

0.0411

AC:

10284

AN:

250264

AF XY:

0.0390

show subpopulations

Gnomad AFR exome

AF:

0.0723

Gnomad AMR exome

AF:

0.0413

Gnomad ASJ exome

AF:

0.0301

Gnomad EAS exome

AF:

0.0614

Gnomad FIN exome

AF:

0.0610

Gnomad NFE exome

AF:

0.0352

Gnomad OTH exome

AF:

0.0399

GnomAD4 exome

AF:

0.0388

AC:

56713

AN:

1461202

Hom.:

1217

Cov.:

AF XY:

0.0378

AC XY:

27470

AN XY:

726830

show subpopulations

African (AFR)

AF:

0.0710

AC:

2377

AN:

33480

American (AMR)

AF:

0.0406

AC:

1815

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0315

AC:

824

AN:

26132

East Asian (EAS)

AF:

0.0615

AC:

2443

AN:

39700

South Asian (SAS)

AF:

0.0225

AC:

1938

AN:

86256

European-Finnish (FIN)

AF:

0.0607

AC:

3202

AN:

52762

Middle Eastern (MID)

AF:

0.0361

AC:

208

AN:

5768

European-Non Finnish (NFE)

AF:

0.0371

AC:

41282

AN:

1111994

Other (OTH)

AF:

0.0434

AC:

2624

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

3317

6634

9950

13267

16584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1660

3320

4980

6640

8300

<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:

0.0486

AC:

7400

AN:

152268

Hom.:

184

Cov.:

AF XY:

0.0486

AC XY:

3617

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0683

AC:

2838

AN:

41534

American (AMR)

AF:

0.0477

AC:

730

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

115

AN:

3470

East Asian (EAS)

AF:

0.0582

AC:

301

AN:

5172

South Asian (SAS)

AF:

0.0290

AC:

140

AN:

4826

European-Finnish (FIN)

AF:

0.0544

AC:

577

AN:

10608

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0379

AC:

2576

AN:

68032

Other (OTH)

AF:

0.0402

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

357

713

1070

1426

1783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0384

Hom.:

435

Bravo

AF:

0.0476

TwinsUK

AF:

0.0410

AC:

152

ALSPAC

AF:

0.0384

AC:

148

ESP6500AA

AF:

0.0706

AC:

311

ESP6500EA

AF:

0.0341

AC:

293

ExAC

AF:

0.0403

AC:

4898

Asia WGS

AF:

0.0530

AC:

187

AN:

3478

EpiCase

AF:

0.0364

EpiControl

AF:

0.0359

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

May 12, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 29, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Retinal dystrophy

Uncertain:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Retinitis Pigmentosa, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Stargardt Disease, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCA4-related disorder

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cone-Rod Dystrophy, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Macular degeneration

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

Benign

0.078

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

T;D

MetaRNN

Benign

0.018

T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.8

M;.

PhyloP100

3.2

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.2

N;.

REVEL

Pathogenic

0.72

Sift

Benign

0.061

T;.

Sift4G

Uncertain

0.049

D;.

Polyphen

1.0

D;.

Vest4

0.42

MPC

0.12

ClinPred

0.041

GERP RS

4.0

Varity_R

0.058

gMVP

0.85

Mutation Taster

=79/21

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over