rs55665437

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000350.3(ABCA4):c.*136G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00779 in 1,176,140 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene ABCA4 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0053 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0082 ( 93 hom. )

Consequence

ABCA4
NM_000350.3 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.141

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 1-93993101-C-T is Benign according to our data. Variant chr1-93993101-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 298218.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0053 (806/152150) while in subpopulation SAS AF = 0.0289 (139/4806). AF 95% confidence interval is 0.025. There are 4 homozygotes in GnomAd4. There are 402 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

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.*136G>A		3_prime_UTR	Exon 50 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.*136G>A		3_prime_UTR	Exon 49 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.*136G>A		3_prime_UTR	Exon 50 of 50	ENSP00000359245.3	P78363

Frequencies

GnomAD3 genomes

AF:

0.00530

AC:

806

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0285

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00787

Gnomad OTH

AF:

0.00527

GnomAD4 exome

AF:

0.00817

AC:

8361

AN:

1023990

Hom.:

Cov.:

AF XY:

0.00916

AC XY:

4799

AN XY:

524056

show subpopulations

African (AFR)

AF:

0.000781

AC:

AN:

24326

American (AMR)

AF:

0.00228

AC:

AN:

37772

Ashkenazi Jewish (ASJ)

AF:

0.00106

AC:

AN:

22586

East Asian (EAS)

AF:

0.00

AC:

AN:

35952

South Asian (SAS)

AF:

0.0293

AC:

2165

AN:

73926

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

47024

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

3492

European-Non Finnish (NFE)

AF:

0.00764

AC:

5598

AN:

733158

Other (OTH)

AF:

0.00776

AC:

355

AN:

45754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

394

788

1182

1576

1970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<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:

0.00530

AC:

806

AN:

152150

Hom.:

Cov.:

AF XY:

0.00540

AC XY:

402

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41520

American (AMR)

AF:

0.00222

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.0289

AC:

139

AN:

4806

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00787

AC:

535

AN:

67986

Other (OTH)

AF:

0.00474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00711

Hom.:

Bravo

AF:

0.00442

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

ABCA4-related disorder (1)

Cone-Rod Dystrophy, Recessive (1)

Macular degeneration (1)

not provided (1)

Retinitis Pigmentosa, Recessive (1)

Stargardt Disease, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.5

(source)

DANN

Benign

0.81

PhyloP100

-0.14

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over