NM_000350.3:c.6285T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000350.3(ABCA4):c.6285T>C(p.Asp2095Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,612,464 control chromosomes in the GnomAD database, including 28,639 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 9736 hom., cov: 32)

Exomes 𝑓: 0.13 ( 18903 hom. )

Consequence

ABCA4
NM_000350.3 splice_region, synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 1.76

Publications

25 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

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 1-94001103-A-G is Benign according to our data. Variant chr1-94001103-A-G is described in ClinVar as Benign. ClinVar VariationId is 99444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.76 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.64 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.6285T>C	p.Asp2095Asp	splice_region synonymous	Exon 46 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.6063T>C	p.Asp2021Asp	splice_region synonymous	Exon 45 of 49	NP_001412253.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA4	ENST00000370225.4	TSL:1 MANE Select	c.6285T>C	p.Asp2095Asp	splice_region synonymous	Exon 46 of 50	ENSP00000359245.3	P78363

Frequencies

GnomAD3 genomes

AF:

0.268

AC:

40724

AN:

151848

Hom.:

9717

Cov.:

show subpopulations

Gnomad AFR

AF:

0.646

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.184

Gnomad EAS

AF:

0.151

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.0723

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.249

GnomAD2 exomes

AF:

0.158

AC:

39517

AN:

250446

AF XY:

0.151

show subpopulations

Gnomad AFR exome

AF:

0.665

Gnomad AMR exome

AF:

0.0987

Gnomad ASJ exome

AF:

0.193

Gnomad EAS exome

AF:

0.149

Gnomad FIN exome

AF:

0.0737

Gnomad NFE exome

AF:

0.115

Gnomad OTH exome

AF:

0.147

GnomAD4 exome

AF:

0.133

AC:

194137

AN:

1460498

Hom.:

18903

Cov.:

AF XY:

0.133

AC XY:

96606

AN XY:

726550

show subpopulations

African (AFR)

AF:

0.676

AC:

22628

AN:

33464

American (AMR)

AF:

0.104

AC:

4651

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.195

AC:

5092

AN:

26126

East Asian (EAS)

AF:

0.145

AC:

5741

AN:

39696

South Asian (SAS)

AF:

0.166

AC:

14296

AN:

86220

European-Finnish (FIN)

AF:

0.0755

AC:

4008

AN:

53108

Middle Eastern (MID)

AF:

0.238

AC:

1364

AN:

5742

European-Non Finnish (NFE)

AF:

0.114

AC:

126428

AN:

1111076

Other (OTH)

AF:

0.165

AC:

9929

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

8445

16889

25334

33778

42223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4912

9824

14736

19648

24560

<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:

0.268

AC:

40791

AN:

151966

Hom.:

9736

Cov.:

AF XY:

0.263

AC XY:

19512

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.646

AC:

26741

AN:

41384

American (AMR)

AF:

0.149

AC:

2282

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.184

AC:

639

AN:

3470

East Asian (EAS)

AF:

0.151

AC:

779

AN:

5156

South Asian (SAS)

AF:

0.164

AC:

790

AN:

4818

European-Finnish (FIN)

AF:

0.0723

AC:

766

AN:

10594

Middle Eastern (MID)

AF:

0.269

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.117

AC:

7977

AN:

67964

Other (OTH)

AF:

0.251

AC:

529

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1090

2181

3271

4362

5452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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.:

1108

Bravo

AF:

0.292

Asia WGS

AF:

0.209

AC:

730

AN:

3478

EpiCase

AF:

0.131

EpiControl

AF:

0.132

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

ABCA4-related disorder (1)

Cone-Rod Dystrophy, Recessive (1)

Macular degeneration (1)

Retinal dystrophy (1)

Retinitis Pigmentosa, Recessive (1)

Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.30

(source)

DANN

Benign

0.73

PhyloP100

1.8

Mutation Taster

=78/22

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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