rs3112831

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1268A>G(p.His423Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,610,992 control chromosomes in the GnomAD database, including 72,755 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H423Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.26 ( 5454 hom., cov: 28)

Exomes 𝑓: 0.30 ( 67301 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: 2.40

Publications

68 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:

LOC124904222 (HGNC:):

LOC124904222 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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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=0.035622448).

BP6

Variant 1-94078678-T-C is Benign according to our data. Variant chr1-94078678-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.1268A>G	p.His423Arg	missense_variant	Exon 10 of 50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.1268A>G	p.His423Arg	missense_variant	Exon 10 of 49		NP_001412253.1
LOC124904222	XR_007066231.1 link	n.203-5051T>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 link	c.1268A>G	p.His423Arg	missense_variant	Exon 10 of 50	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000649773.1 link	c.1268A>G	p.His423Arg	missense_variant	Exon 10 of 19			ENSP00000496882.1		A0A3B3IRV8

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

39029

AN:

151382

Hom.:

5443

Cov.:

show subpopulations

Gnomad AFR

AF:

0.163

Gnomad AMI

AF:

0.239

Gnomad AMR

AF:

0.279

Gnomad ASJ

AF:

0.250

Gnomad EAS

AF:

0.260

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.318

Gnomad OTH

AF:

0.265

GnomAD2 exomes

AF:

0.255

AC:

64225

AN:

251484

AF XY:

0.254

show subpopulations

Gnomad AFR exome

AF:

0.162

Gnomad AMR exome

AF:

0.219

Gnomad ASJ exome

AF:

0.234

Gnomad EAS exome

AF:

0.246

Gnomad FIN exome

AF:

0.250

Gnomad NFE exome

AF:

0.308

Gnomad OTH exome

AF:

0.271

GnomAD4 exome

AF:

0.299

AC:

435950

AN:

1459492

Hom.:

67301

Cov.:

AF XY:

0.294

AC XY:

213617

AN XY:

726128

show subpopulations

African (AFR)

AF:

0.162

AC:

5426

AN:

33458

American (AMR)

AF:

0.227

AC:

10171

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

6194

AN:

26120

East Asian (EAS)

AF:

0.254

AC:

10073

AN:

39682

South Asian (SAS)

AF:

0.167

AC:

14362

AN:

86226

European-Finnish (FIN)

AF:

0.253

AC:

13511

AN:

53390

Middle Eastern (MID)

AF:

0.171

AC:

982

AN:

5758

European-Non Finnish (NFE)

AF:

0.323

AC:

358535

AN:

1109836

Other (OTH)

AF:

0.277

AC:

16696

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

14084

28168

42251

56335

70419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11588

23176

34764

46352

57940

<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:

0.258

AC:

39076

AN:

151500

Hom.:

5454

Cov.:

AF XY:

0.254

AC XY:

18812

AN XY:

73986

show subpopulations

African (AFR)

AF:

0.164

AC:

6759

AN:

41300

American (AMR)

AF:

0.280

AC:

4248

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

866

AN:

3462

East Asian (EAS)

AF:

0.260

AC:

1334

AN:

5124

South Asian (SAS)

AF:

0.175

AC:

838

AN:

4788

European-Finnish (FIN)

AF:

0.254

AC:

2658

AN:

10454

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.318

AC:

21567

AN:

67884

Other (OTH)

AF:

0.265

AC:

557

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1413

2826

4240

5653

7066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

412

824

1236

1648

2060

<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:

0.293

Hom.:

25776

Bravo

AF:

0.256

TwinsUK

AF:

0.328

AC:

1216

ALSPAC

AF:

0.304

AC:

1170

ESP6500AA

AF:

0.165

AC:

729

ESP6500EA

AF:

0.309

AC:

2661

ExAC

AF:

0.255

AC:

30988

Asia WGS

AF:

0.236

AC:

819

AN:

3478

EpiCase

AF:

0.303

EpiControl

AF:

0.304

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Aug 31, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Likely 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

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:5

May 19, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 10, 2012

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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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. -

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

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

0.048

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

4.8

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.077

T;T

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.5

N;.

PhyloP100

2.4

PrimateAI

Benign

0.41

PROVEAN

Benign

2.1

N;.

REVEL

Uncertain

0.29

Sift

Benign

0.36

T;.

Sift4G

Benign

0.28

T;.

Polyphen

0.0

B;.

Vest4

0.038

MPC

0.10

ClinPred

0.014

GERP RS

5.5

Varity_R

0.076

gMVP

0.64

Mutation Taster

=72/28

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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