chr1-94060488-A-G

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.2160+49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 1,560,890 control chromosomes in the GnomAD database, including 2,075 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene ABCA4 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.054 ( 258 hom., cov: 32)

Exomes 𝑓: 0.049 ( 1817 hom. )

Consequence

ABCA4
NM_000350.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.238

Publications

2 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
age related macular degeneration 2
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ABCA4 links:

Genome browser will be placed here

ACMG classification

Specifications for ABCA4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 1-94060488-A-G is Benign according to our data. Variant chr1-94060488-A-G is described in ClinVar as Benign. ClinVar VariationId is 255917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0715 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	NM_000350.3	MANE Select	c.2160+49T>C		intron	N/A	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.2160+49T>C		intron	N/A	NP_001412253.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.2160+49T>C	intron	N/A	ENSP00000359245.3	P78363
ABCA4	ENST00000649773.1		c.2160+49T>C	intron	N/A	ENSP00000496882.1	A0A3B3IRV8
ABCA4	ENST00000472033.1	TSL:3	n.280+49T>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0541

AC:

8230

AN:

152176

Hom.:

250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0682

Gnomad AMI

AF:

0.0352

Gnomad AMR

AF:

0.0746

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.0375

Gnomad SAS

AF:

0.0595

Gnomad FIN

AF:

0.0395

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0461

Gnomad OTH

AF:

0.0554

GnomAD2 exomes

AF:

0.0499

AC:

12426

AN:

249258

AF XY:

0.0492

show subpopulations

Gnomad AFR exome

AF:

0.0691

Gnomad AMR exome

AF:

0.0719

Gnomad ASJ exome

AF:

0.0221

Gnomad EAS exome

AF:

0.0404

Gnomad FIN exome

AF:

0.0431

Gnomad NFE exome

AF:

0.0437

Gnomad OTH exome

AF:

0.0442

GnomAD4 exome

AF:

0.0490

AC:

69055

AN:

1408596

Hom.:

1817

Cov.:

AF XY:

0.0487

AC XY:

34257

AN XY:

704014

show subpopulations

African (AFR)

AF:

0.0720

AC:

2324

AN:

32256

American (AMR)

AF:

0.0711

AC:

3173

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

549

AN:

25818

East Asian (EAS)

AF:

0.0427

AC:

1684

AN:

39400

South Asian (SAS)

AF:

0.0561

AC:

4765

AN:

84884

European-Finnish (FIN)

AF:

0.0440

AC:

2348

AN:

53392

Middle Eastern (MID)

AF:

0.0373

AC:

154

AN:

4132

European-Non Finnish (NFE)

AF:

0.0480

AC:

51176

AN:

1065594

Other (OTH)

AF:

0.0492

AC:

2882

AN:

58520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

3587

7174

10761

14348

17935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1988

3976

5964

7952

9940

<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:

0.0543

AC:

8266

AN:

152294

Hom.:

258

Cov.:

AF XY:

0.0545

AC XY:

4056

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0687

AC:

2855

AN:

41552

American (AMR)

AF:

0.0751

AC:

1149

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

AN:

3472

East Asian (EAS)

AF:

0.0376

AC:

195

AN:

5184

South Asian (SAS)

AF:

0.0597

AC:

288

AN:

4822

European-Finnish (FIN)

AF:

0.0395

AC:

419

AN:

10620

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0461

AC:

3135

AN:

68028

Other (OTH)

AF:

0.0553

AC:

117

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

405

810

1215

1620

2025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0473

Hom.:

Bravo

AF:

0.0574

Asia WGS

AF:

0.0490

AC:

170

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

6.0

(source)

DANN

Benign

0.68

PhyloP100

0.24

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over