NM_000350.3:c.1240-14C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000350.3(ABCA4):c.1240-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,576,202 control chromosomes in the GnomAD database, including 172,216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 17130 hom., cov: 31)

Exomes 𝑓: 0.46 ( 155086 hom. )

Consequence

ABCA4
NM_000350.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: 0.185

Publications

16 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 1-94078720-G-A is Benign according to our data. Variant chr1-94078720-G-A is described in ClinVar as Benign. ClinVar VariationId is 99037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.1240-14C>T	intron_variant	Intron 9 of 49	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.1240-14C>T	intron_variant	Intron 9 of 48		NP_001412253.1
LOC124904222	XR_007066231.1 link	n.203-5009G>A	intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 link	c.1240-14C>T		intron_variant	Intron 9 of 49	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000649773.1 link	c.1240-14C>T		intron_variant	Intron 9 of 18			ENSP00000496882.1		A0A3B3IRV8

Frequencies

GnomAD3 genomes

AF:

0.474

AC:

71857

AN:

151692

Hom.:

17122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.478

Gnomad AMI

AF:

0.578

Gnomad AMR

AF:

0.514

Gnomad ASJ

AF:

0.534

Gnomad EAS

AF:

0.570

Gnomad SAS

AF:

0.483

Gnomad FIN

AF:

0.458

Gnomad MID

AF:

0.478

Gnomad NFE

AF:

0.452

Gnomad OTH

AF:

0.459

GnomAD2 exomes

AF:

0.486

AC:

122181

AN:

251464

AF XY:

0.481

show subpopulations

Gnomad AFR exome

AF:

0.475

Gnomad AMR exome

AF:

0.562

Gnomad ASJ exome

AF:

0.545

Gnomad EAS exome

AF:

0.564

Gnomad FIN exome

AF:

0.458

Gnomad NFE exome

AF:

0.455

Gnomad OTH exome

AF:

0.485

GnomAD4 exome

AF:

0.464

AC:

661409

AN:

1424392

Hom.:

155086

Cov.:

AF XY:

0.464

AC XY:

329854

AN XY:

710954

show subpopulations

African (AFR)

AF:

0.473

AC:

15530

AN:

32858

American (AMR)

AF:

0.556

AC:

24829

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.548

AC:

14223

AN:

25978

East Asian (EAS)

AF:

0.582

AC:

22987

AN:

39514

South Asian (SAS)

AF:

0.467

AC:

40025

AN:

85636

European-Finnish (FIN)

AF:

0.459

AC:

24503

AN:

53398

Middle Eastern (MID)

AF:

0.469

AC:

2689

AN:

5738

European-Non Finnish (NFE)

AF:

0.453

AC:

488211

AN:

1077414

Other (OTH)

AF:

0.480

AC:

28412

AN:

59176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

15726

31451

47177

62902

78628

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14574

29148

43722

58296

72870

<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:

0.474

AC:

71902

AN:

151810

Hom.:

17130

Cov.:

AF XY:

0.475

AC XY:

35251

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.478

AC:

19780

AN:

41350

American (AMR)

AF:

0.514

AC:

7833

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.534

AC:

1853

AN:

3470

East Asian (EAS)

AF:

0.569

AC:

2926

AN:

5144

South Asian (SAS)

AF:

0.483

AC:

2319

AN:

4802

European-Finnish (FIN)

AF:

0.458

AC:

4823

AN:

10520

Middle Eastern (MID)

AF:

0.480

AC:

141

AN:

294

European-Non Finnish (NFE)

AF:

0.452

AC:

30724

AN:

67954

Other (OTH)

AF:

0.462

AC:

978

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1897

3795

5692

7590

9487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

664

1328

1992

2656

3320

<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:

0.464

Hom.:

13472

Bravo

AF:

0.480

Asia WGS

AF:

0.544

AC:

1893

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Nov 07, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 16, 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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

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

- -

not provided

Benign:2Other:1

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Age related macular degeneration 2

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCA4-related disorder

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Severe early-childhood-onset retinal dystrophy

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Retinitis pigmentosa 19

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cone-rod dystrophy 3

Benign:1

Jul 14, 2021

Genome-Nilou Lab

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

-0.66

CADD

Benign

9.8

(source)

DANN

Benign

0.77

PhyloP100

0.18

Mutation Taster

=94/6

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