chr1-94062803-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000350.3(ABCA4):c.1761-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,585,642 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 12 hom., cov: 32)

Exomes 𝑓: 0.017 ( 243 hom. )

Consequence

ABCA4
NM_000350.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 0.0770

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

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=-0.86).

BP6

Variant 1-94062803-C-T is Benign according to our data. Variant chr1-94062803-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0121 (1848/152240) while in subpopulation NFE AF = 0.0194 (1320/68014). AF 95% confidence interval is 0.0185. There are 12 homozygotes in GnomAd4. There are 879 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.1761-50G>A		intron_variant	Intron 12 of 49	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.1761-50G>A		intron_variant	Intron 12 of 48		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 link	c.1761-50G>A		intron_variant	Intron 12 of 49	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000649773.1 link	c.1761-50G>A		intron_variant	Intron 12 of 18			ENSP00000496882.1		A0A3B3IRV8

Frequencies

GnomAD3 genomes

AF:

0.0121

AC:

1847

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00309

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00963

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00788

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0194

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0141

AC:

3236

AN:

228846

AF XY:

0.0144

show subpopulations

Gnomad AFR exome

AF:

0.00253

Gnomad AMR exome

AF:

0.0103

Gnomad ASJ exome

AF:

0.0259

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00898

Gnomad NFE exome

AF:

0.0202

Gnomad OTH exome

AF:

0.0216

GnomAD4 exome

AF:

0.0168

AC:

24061

AN:

1433402

Hom.:

243

Cov.:

AF XY:

0.0168

AC XY:

11999

AN XY:

712904

show subpopulations

African (AFR)

AF:

0.00240

AC:

AN:

32900

American (AMR)

AF:

0.0108

AC:

467

AN:

43334

Ashkenazi Jewish (ASJ)

AF:

0.0244

AC:

630

AN:

25776

East Asian (EAS)

AF:

0.0000509

AC:

AN:

39276

South Asian (SAS)

AF:

0.00957

AC:

806

AN:

84212

European-Finnish (FIN)

AF:

0.0116

AC:

591

AN:

51062

Middle Eastern (MID)

AF:

0.0276

AC:

158

AN:

5720

European-Non Finnish (NFE)

AF:

0.0186

AC:

20342

AN:

1091594

Other (OTH)

AF:

0.0166

AC:

986

AN:

59528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1266

2532

3798

5064

6330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

738

1476

2214

2952

3690

<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:

0.0121

AC:

1848

AN:

152240

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

879

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00310

AC:

129

AN:

41548

American (AMR)

AF:

0.00961

AC:

147

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00789

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0101

AC:

107

AN:

10610

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0194

AC:

1320

AN:

68014

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

190

285

380

475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0187

Hom.:

Bravo

AF:

0.0117

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely 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

-0.86

CADD

Benign

1.1

(source)

DANN

Benign

0.80

PhyloP100

0.077

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over