dbSNP rs1800553: ABCA4:p.Gly1961Glu (chr1-94008251-C-T) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 18P and 2B. PS3PM1PM5PP2PP3PP5_Very_StrongBP4BS1_Supporting

The NM_000350.3(ABCA4):c.5882G>A(p.Gly1961Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00341 in 1,614,012 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000494247: in vitro functional assays demonstrated that this variant resulted in decreased ATP-binding capacity and ATP hydrolysis, despite an increase of the total amount of ABCA4 protein (Sun et al., 2000)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1961R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 41 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:67U:1B:1O:4

Conservation

PhyloP100: 5.88

Publications

320 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: Pathogenic. The variant received 16 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000494247: in vitro functional assays demonstrated that this variant resulted in decreased ATP-binding capacity and ATP hydrolysis, despite an increase of the total amount of ABCA4 protein (Sun et al., 2000).; SCV002767263: "This variant has moderate functional evidence supporting abnormal protein function, where transfected cells displayed reduced ATPase activity and substrate binding (PMID: 29847635)."; SCV005881644: Study has shown the variant affects the function of the protein (PS3_sup, PMID:29847635).; SCV001573158: Functional studies demonstrate that this variant results in reduced ATPase activity9,10.; SCV000321357: Published functional studies demonstrate this variant results in reduced ATPase activity (Sun et al., 2000);; SCV001159230: Functional studies show this variant lies in a critical functional domain and results in reduced function of this variant protein compared to the wild type protein (Garces 2018, Sun 2000).; SCV001229561: Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087, 29847635).; SCV001549384: Further, functional analysis has demonstrated that this variant results in reduced basal and retinal-stimulated ATPase activities compared to control (Sun_2000_PMID:11017087).; SCV000359235: Functional studies demonstrated that the p.Gly1961Glu variant protein resulted in reduced ATPase activity and ATP binding, while maintaining expression levels comparable to wild type, which is consistent with a mild phenotype. Additionally, the variant protein ATPase activity was inhibited by all-trans retinal, in contrast to the stimulation seen in wild type (Sun et al. 2000; Burke et al 2012a).; SCV002754519: Functional studies have shown that this variant alters ABCA4 protein function (PMID: 11017087, 29847635) (PS3).; SCV000221171: "In vitro functional studies support an impact on protein function (Sun 2000 PMID:11017087)."; SCV005329588: Functional studies indicate that the p.Gly1961Glu variant results in reduced ATPase activity and ATP binding, therefore, affecting ABCA4 protein function (Garces F, et al., 2018; Burke TR, et al., 2012).; SCV002520430: Through a review of available evidence we were able to apply the following criteria: PS3, PM5, PP3, PP5. https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94008252-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 236140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 578 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: -0.65813 (below the threshold of 3.09). Trascript score misZ: 1.3628 (below the threshold of 3.09). GenCC associations: The gene is linked to severe early-childhood-onset retinal dystrophy, retinitis pigmentosa, age related macular degeneration 2, retinitis pigmentosa 19, cone-rod dystrophy 3, ABCA4-related retinopathy, Stargardt disease, cone-rod dystrophy.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

PP5

Variant 1-94008251-C-T is Pathogenic according to our data. Variant chr1-94008251-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7888.Status of the report is reviewed_by_expert_panel, 3 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.013598174). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00311 (473/152210) while in subpopulation SAS AF = 0.0127 (61/4814). AF 95% confidence interval is 0.0101. There are 3 homozygotes in GnomAd4. There are 239 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.5882G>A	p.Gly1961Glu	missense	Exon 42 of 50	NP_000341.2	P78363
	ABCA4	NM_001425324.1		c.5660G>A	p.Gly1887Glu	missense	Exon 41 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.5882G>A	p.Gly1961Glu	missense	Exon 42 of 50	ENSP00000359245.3	P78363
	ABCA4	ENST00000465352.1	TSL:5	n.298G>A		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes

AF:

0.00311

AC:

473

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.0239

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0127

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00325

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00470

AC:

1181

AN:

251452

AF XY:

0.00537

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.0237

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00348

Gnomad OTH exome

AF:

0.00570

GnomAD4 exome

AF:

0.00344

AC:

5025

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

2792

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33480

American (AMR)

AF:

0.00177

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

581

AN:

26134

East Asian (EAS)

AF:

0.000529

AC:

AN:

39700

South Asian (SAS)

AF:

0.0131

AC:

1134

AN:

86246

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0205

AC:

118

AN:

5768

European-Non Finnish (NFE)

AF:

0.00239

AC:

2661

AN:

1111936

Other (OTH)

AF:

0.00546

AC:

330

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.414

Heterozygous variant carriers

278

556

834

1112

1390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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:

0.00311

AC:

473

AN:

152210

Hom.:

Cov.:

AF XY:

0.00321

AC XY:

239

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000554

AC:

AN:

41528

American (AMR)

AF:

0.00379

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0239

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.0127

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00325

AC:

221

AN:

68020

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00389

Hom.:

Bravo

AF:

0.00284

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00505

AC:

613

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00480

EpiControl

AF:

0.00451

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Severe early-childhood-onset retinal dystrophy (22)

not provided (12)

Cone-rod dystrophy 3 (5)

Stargardt disease (5)

Retinal dystrophy (4)

ABCA4-related disorder (3)

Age related macular degeneration 2 (3)

Macular dystrophy (3)

Retinitis pigmentosa 19 (3)

ABCA4-related retinopathy (2)

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19 (2)

Cone dystrophy (1)

Inborn genetic diseases (1)

not specified (1)

Retinal disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

-0.12

PhyloP100

5.9

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.96

MVP

0.95

MPC

0.53

ClinPred

0.071

GERP RS

5.3

Varity_R

0.93

gMVP

0.95

Mutation Taster

=11/89

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

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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