1-94032007-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000350.3(ABCA4):c.3899G>A(p.Arg1300Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,613,304 control chromosomes in the GnomAD database, including 183 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1300L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 105 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 78 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.0150

Publications

21 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 -19 ACMG points.

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=0.0024959445).

BP6

Variant 1-94032007-C-T is Benign according to our data. Variant chr1-94032007-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 99246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.3899G>A	p.Arg1300Gln	missense_variant	Exon 27 of 50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.3677G>A	p.Arg1226Gln	missense_variant	Exon 26 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 link	c.3899G>A	p.Arg1300Gln	missense_variant	Exon 27 of 50	1	NM_000350.3	ENSP00000359245.3		P78363

Frequencies

GnomAD3 genomes

AF:

0.0194

AC:

2948

AN:

151986

Hom.:

105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0665

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00806

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000832

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.00514

AC:

1278

AN:

248808

AF XY:

0.00392

show subpopulations

Gnomad AFR exome

AF:

0.0675

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000668

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00218

AC:

3191

AN:

1461200

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

1413

AN XY:

726916

show subpopulations

African (AFR)

AF:

0.0683

AC:

2285

AN:

33478

American (AMR)

AF:

0.00360

AC:

161

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000336

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52740

Middle Eastern (MID)

AF:

0.00537

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000334

AC:

371

AN:

1112004

Other (OTH)

AF:

0.00520

AC:

314

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

185

370

555

740

925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0194

AC:

2956

AN:

152104

Hom.:

105

Cov.:

AF XY:

0.0184

AC XY:

1369

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0665

AC:

2757

AN:

41484

American (AMR)

AF:

0.00805

AC:

123

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000833

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

67980

Other (OTH)

AF:

0.0175

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

134

268

401

535

669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00618

Hom.:

Bravo

AF:

0.0221

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0617

AC:

272

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00636

AC:

772

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 30, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

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

- -

not specified

Benign:2

Mar 18, 2015

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. -

Jun 11, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Macular dystrophy

Benign:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:research

- -

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

0.071

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.36

CADD

Benign

6.3

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.091

LIST_S2

Benign

0.70

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.55

.;N

PhyloP100

0.015

PrimateAI

Benign

0.19

PROVEAN

Benign

0.13

.;N

REVEL

Benign

0.21

Sift

Benign

0.41

.;T

Sift4G

Benign

0.65

T;T

Polyphen

0.14

.;B

Vest4

0.18

MVP

0.69

MPC

0.097

ClinPred

0.0015

GERP RS

3.0

Varity_R

0.048

gMVP

0.24

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

1-94032007-C-T

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