rs1553188682

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The ENST00000370225.4(ABCA4):ā€‹c.4727T>Gā€‹(p.Leu1576Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1576F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

ABCA4
ENST00000370225.4 missense

Scores

5
9
5

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.35
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000370225.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.961
PP5
Variant 1-94021892-A-C is Pathogenic according to our data. Variant chr1-94021892-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438097.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-94021892-A-C is described in Lovd as [Likely_pathogenic]. Variant chr1-94021892-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ABCA4NM_000350.3 linkuse as main transcriptc.4727T>G p.Leu1576Arg missense_variant 33/50 ENST00000370225.4 NP_000341.2
ABCA4XM_047416704.1 linkuse as main transcriptc.4505T>G p.Leu1502Arg missense_variant 32/49 XP_047272660.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ABCA4ENST00000370225.4 linkuse as main transcriptc.4727T>G p.Leu1576Arg missense_variant 33/501 NM_000350.3 ENSP00000359245 P1
ABCA4ENST00000460514.1 linkuse as main transcriptn.221T>G non_coding_transcript_exon_variant 4/75

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461894
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 10, 2023This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1576 of the ABCA4 protein (p.Leu1576Arg). This missense change has been observed in individual(s) with Stargardt Disease (PMID: 28041643). ClinVar contains an entry for this variant (Variation ID: 438097). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.36
T;D
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.74
T;T
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Benign
1.4
.;L
MutationTaster
Benign
0.98
D
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-3.4
.;D
REVEL
Uncertain
0.63
Sift
Uncertain
0.0010
.;D
Sift4G
Benign
0.075
T;D
Polyphen
0.83
.;P
Vest4
0.57
MutPred
0.84
.;Gain of methylation at L1576 (P = 0.023);
MVP
0.94
MPC
0.30
ClinPred
0.95
D
GERP RS
6.2
Varity_R
0.78
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553188682; hg19: chr1-94487448; COSMIC: COSV64674232; COSMIC: COSV64674232; API