chr1-94008340-G-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.5836-43C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,583,010 control chromosomes in the GnomAD database, including 25,537 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2935 hom., cov: 32)

Exomes 𝑓: 0.18 ( 22602 hom. )

Consequence

ABCA4
NM_000350.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.277

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 1-94008340-G-T is Benign according to our data. Variant chr1-94008340-G-T is described in CliVar as Benign. Clinvar id is 255925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94008340-G-T is described in CliVar as Benign. Clinvar id is 255925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94008340-G-T is described in CliVar as Benign. Clinvar id is 255925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.5836-43C>A		intron_variant	Intron 41 of 49	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.5614-43C>A		intron_variant	Intron 40 of 48		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 link	c.5836-43C>A		intron_variant	Intron 41 of 49	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000465352.1 link	n.252-43C>A		intron_variant	Intron 2 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.193

AC:

29315

AN:

152084

Hom.:

2924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.236

Gnomad AMI

AF:

0.137

Gnomad AMR

AF:

0.165

Gnomad ASJ

AF:

0.212

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.172

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.179

GnomAD2 exomes

AF:

0.172

AC:

43169

AN:

250740

AF XY:

0.170

show subpopulations

Gnomad AFR exome

AF:

0.235

Gnomad AMR exome

AF:

0.155

Gnomad ASJ exome

AF:

0.202

Gnomad EAS exome

AF:

0.127

Gnomad FIN exome

AF:

0.174

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.175

AC:

250587

AN:

1430808

Hom.:

22602

Cov.:

AF XY:

0.174

AC XY:

124243

AN XY:

713670

show subpopulations

African (AFR)

AF:

0.242

AC:

7916

AN:

32702

American (AMR)

AF:

0.159

AC:

7094

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

5234

AN:

25894

East Asian (EAS)

AF:

0.135

AC:

5353

AN:

39554

South Asian (SAS)

AF:

0.131

AC:

11262

AN:

85678

European-Finnish (FIN)

AF:

0.176

AC:

9411

AN:

53364

Middle Eastern (MID)

AF:

0.168

AC:

960

AN:

5700

European-Non Finnish (NFE)

AF:

0.178

AC:

193065

AN:

1083896

Other (OTH)

AF:

0.173

AC:

10292

AN:

59390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

9991

19982

29973

39964

49955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6638

13276

19914

26552

33190

<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:

0.193

AC:

29376

AN:

152202

Hom.:

2935

Cov.:

AF XY:

0.190

AC XY:

14139

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.236

AC:

9815

AN:

41502

American (AMR)

AF:

0.165

AC:

2523

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

734

AN:

3466

East Asian (EAS)

AF:

0.131

AC:

677

AN:

5170

South Asian (SAS)

AF:

0.128

AC:

620

AN:

4826

European-Finnish (FIN)

AF:

0.172

AC:

1826

AN:

10610

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.186

AC:

12627

AN:

68006

Other (OTH)

AF:

0.183

AC:

386

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1222

2443

3665

4886

6108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

322

644

966

1288

1610

<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:

0.181

Hom.:

4015

Bravo

AF:

0.194

Asia WGS

AF:

0.146

AC:

508

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

- -

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

4.9

(source)

DANN

Benign

0.61

PhyloP100

-0.28

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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