rs1800717

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000350.3(ABCA4):c.6730-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0571 in 1,608,004 control chromosomes in the GnomAD database, including 7,710 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 3492 hom., cov: 33)

Exomes 𝑓: 0.048 ( 4218 hom. )

Consequence

ABCA4
NM_000350.3 splice_region, intron

Scores

Splicing: ADA: 0.00002718

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:2

Conservation

PhyloP100: 0.779

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 1-93996198-A-G is Benign according to our data. Variant chr1-93996198-A-G is described in ClinVar as [Benign]. Clinvar id is 99491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-93996198-A-G is described in Lovd as [Benign]. Variant chr1-93996198-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.6730-3T>C		splice_region_variant, intron_variant	Intron 48 of 49	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.6508-3T>C		splice_region_variant, intron_variant	Intron 47 of 48		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 link	c.6730-3T>C		splice_region_variant, intron_variant	Intron 48 of 49	1	NM_000350.3	ENSP00000359245.3		P78363

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21622

AN:

152132

Hom.:

3478

Cov.:

show subpopulations

Gnomad AFR

AF:

0.399

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.0850

Gnomad ASJ

AF:

0.0617

Gnomad EAS

AF:

0.0227

Gnomad SAS

AF:

0.0541

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0407

Gnomad OTH

AF:

0.125

GnomAD3 exomes

AF:

0.0652

AC:

16361

AN:

250840

Hom.:

1655

AF XY:

0.0582

AC XY:

7885

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.411

Gnomad AMR exome

AF:

0.0566

Gnomad ASJ exome

AF:

0.0680

Gnomad EAS exome

AF:

0.0270

Gnomad SAS exome

AF:

0.0498

Gnomad FIN exome

AF:

0.00591

Gnomad NFE exome

AF:

0.0397

Gnomad OTH exome

AF:

0.0633

GnomAD4 exome

AF:

0.0481

AC:

70066

AN:

1455754

Hom.:

4218

Cov.:

AF XY:

0.0474

AC XY:

34334

AN XY:

724640

show subpopulations

Gnomad4 AFR exome

AF:

0.411

Gnomad4 AMR exome

AF:

0.0601

Gnomad4 ASJ exome

AF:

0.0699

Gnomad4 EAS exome

AF:

0.0229

Gnomad4 SAS exome

AF:

0.0504

Gnomad4 FIN exome

AF:

0.00681

Gnomad4 NFE exome

AF:

0.0375

Gnomad4 OTH exome

AF:

0.0680

GnomAD4 genome

AF:

0.142

AC:

21674

AN:

152250

Hom.:

3492

Cov.:

AF XY:

0.138

AC XY:

10257

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.400

Gnomad4 AMR

AF:

0.0847

Gnomad4 ASJ

AF:

0.0617

Gnomad4 EAS

AF:

0.0226

Gnomad4 SAS

AF:

0.0529

Gnomad4 FIN

AF:

0.00518

Gnomad4 NFE

AF:

0.0407

Gnomad4 OTH

AF:

0.124

Alfa

AF:

0.0678

Hom.:

1503

Bravo

AF:

0.160

Asia WGS

AF:

0.0640

AC:

223

AN:

3478

EpiCase

AF:

0.0497

EpiControl

AF:

0.0504

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:2

Breakthrough Genomics, Breakthrough Genomics

Significance: 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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 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. -

Aug 25, 2014

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stargardt Disease, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCA4-related disorder

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cone-Rod Dystrophy, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Jul 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macular degeneration

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.0

DANN

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000027

dbscSNV1_RF

Benign

0.0040

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over