1-94021729-AAC-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000350.3(ABCA4):c.4774-17_4774-16delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,611,092 control chromosomes in the GnomAD database, including 35,843 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2664 hom., cov: 29)

Exomes 𝑓: 0.21 ( 33179 hom. )

Consequence

ABCA4
NM_000350.3 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.145

Publications

9 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 -16 ACMG points.

BP6

Variant 1-94021729-AAC-A is Benign according to our data. Variant chr1-94021729-AAC-A is described in ClinVar as Benign. ClinVar VariationId is 255923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000350.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	NM_000350.3	MANE Select	c.4774-17_4774-16delGT		intron	N/A	NP_000341.2
	ABCA4	NM_001425324.1		c.4552-17_4552-16delGT		intron	N/A	NP_001412253.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.4774-17_4774-16delGT		intron	N/A	ENSP00000359245.3
	ABCA4	ENST00000460514.1	TSL:5	n.268-17_268-16delGT		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

24797

AN:

152058

Hom.:

2664

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0444

Gnomad AMI

AF:

0.233

Gnomad AMR

AF:

0.207

Gnomad ASJ

AF:

0.212

Gnomad EAS

AF:

0.474

Gnomad SAS

AF:

0.269

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.196

Gnomad OTH

AF:

0.195

GnomAD2 exomes

AF:

0.210

AC:

52124

AN:

248696

AF XY:

0.213

show subpopulations

Gnomad AFR exome

AF:

0.0365

Gnomad AMR exome

AF:

0.186

Gnomad ASJ exome

AF:

0.199

Gnomad EAS exome

AF:

0.480

Gnomad FIN exome

AF:

0.130

Gnomad NFE exome

AF:

0.201

Gnomad OTH exome

AF:

0.214

GnomAD4 exome

AF:

0.205

AC:

299657

AN:

1458916

Hom.:

33179

AF XY:

0.206

AC XY:

149879

AN XY:

725924

show subpopulations

African (AFR)

AF:

0.0373

AC:

1246

AN:

33396

American (AMR)

AF:

0.188

AC:

8403

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

5137

AN:

26080

East Asian (EAS)

AF:

0.444

AC:

17604

AN:

39654

South Asian (SAS)

AF:

0.256

AC:

22075

AN:

86102

European-Finnish (FIN)

AF:

0.136

AC:

7242

AN:

53398

Middle Eastern (MID)

AF:

0.196

AC:

1131

AN:

5764

European-Non Finnish (NFE)

AF:

0.202

AC:

224178

AN:

1109598

Other (OTH)

AF:

0.210

AC:

12641

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

12008

24016

36025

48033

60041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7966

15932

23898

31864

39830

<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:

0.163

AC:

24799

AN:

152176

Hom.:

2664

Cov.:

AF XY:

0.163

AC XY:

12111

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0444

AC:

1845

AN:

41542

American (AMR)

AF:

0.208

AC:

3185

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

737

AN:

3470

East Asian (EAS)

AF:

0.474

AC:

2445

AN:

5160

South Asian (SAS)

AF:

0.269

AC:

1296

AN:

4818

European-Finnish (FIN)

AF:

0.123

AC:

1300

AN:

10608

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.196

AC:

13313

AN:

67964

Other (OTH)

AF:

0.194

AC:

410

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1017

2034

3050

4067

5084

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.168

Hom.:

440

Bravo

AF:

0.164

Asia WGS

AF:

0.349

AC:

1213

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Age related macular degeneration 2 (1)

Cone-rod dystrophy 3 (1)

Cone-Rod Dystrophy, Recessive (1)

Macular degeneration (1)

not specified (1)

Retinitis pigmentosa 19 (1)

Retinitis Pigmentosa, Recessive (1)

Severe early-childhood-onset retinal dystrophy (1)

Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.14

Mutation Taster

=91/9

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over