rs62645958

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM5PP5_Very_StrongBP4

The ENST00000370225.4(ABCA4):​c.71G>A​(p.Arg24His) variant causes a missense change. The variant allele was found at a frequency of 0.0000669 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

ABCA4
ENST00000370225.4 missense

Scores

3
12
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 5.00
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000370225.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-94113063-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 857107.Status of the report is criteria_provided_single_submitter, 1 stars.
PP5
Variant 1-94113062-C-T is Pathogenic according to our data. Variant chr1-94113062-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94113062-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94113062-C-T is described in Lovd as [Pathogenic]. Variant chr1-94113062-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94113062-C-T is described in Lovd as [Likely_benign].
BP4
Computational evidence support a benign effect (MetaRNN=0.17898306). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ABCA4NM_000350.3 linkuse as main transcriptc.71G>A p.Arg24His missense_variant 2/50 ENST00000370225.4 NP_000341.2
ABCA4XM_047416704.1 linkuse as main transcriptc.71G>A p.Arg24His missense_variant 2/49 XP_047272660.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ABCA4ENST00000370225.4 linkuse as main transcriptc.71G>A p.Arg24His missense_variant 2/501 NM_000350.3 ENSP00000359245 P1
ABCA4ENST00000649773.1 linkuse as main transcriptc.71G>A p.Arg24His missense_variant 2/19 ENSP00000496882

Frequencies

GnomAD3 genomes
AF:
0.0000855
AC:
13
AN:
152022
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00135
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000179
AC:
45
AN:
250860
Hom.:
0
AF XY:
0.000147
AC XY:
20
AN XY:
135682
show subpopulations
Gnomad AFR exome
AF:
0.0000618
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00147
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000529
Gnomad OTH exome
AF:
0.000818
GnomAD4 exome
AF:
0.0000650
AC:
95
AN:
1461704
Hom.:
0
Cov.:
34
AF XY:
0.0000646
AC XY:
47
AN XY:
727154
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000554
Gnomad4 SAS exome
AF:
0.000209
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000234
Gnomad4 OTH exome
AF:
0.000315
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152140
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
9
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000723
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00135
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000193
Hom.:
0
Bravo
AF:
0.0000945
ExAC
AF:
0.000189
AC:
23
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3Other:1
Likely pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2024This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 24 of the ABCA4 protein (p.Arg24His). This variant is present in population databases (rs62645958, gnomAD 0.1%). This missense change has been observed in individuals with retinopathy (PMID: 9973280, 27820952, 31015497). ClinVar contains an entry for this variant (Variation ID: 99498). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg24 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15494742, 28559085, 29162642, 30093795). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification providedliterature onlyRetina International-- -
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 30, 2020- -
Retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsJul 23, 2019- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2016- -
ABCA4-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJul 31, 2017Across a selection of literature, the ABCA4 c.71G>A (p.Arg24His) missense variant has been reported in a compound heterozygous state in five individuals with Stargardt disease (STGD) as well as in a heterozygous state in one individual (also with STGD) where a second variant was not identified (Lewis et al., 1999; Fujinami et al., 2013; Chacón-Camacho et al., 2013). Four of the compound heterozygous individuals belong to the same family and demonstrated segregation of the disease phenotype with the p.Arg24His variant. The p.Arg24His variant was absent from 440 control chromosomes and is reported at a frequency of 0.002091 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg24His variant is classified as likely pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingJuno Genomics, Hangzhou Juno Genomics, Inc-PM2_Supporting+PP3_Moderate+PM3_Strong+PP1_Moderate+PP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.71
D;.
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.81
T;T
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.18
T;T
MetaSVM
Uncertain
0.69
D
MutationAssessor
Uncertain
2.9
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-2.8
D;.
REVEL
Pathogenic
0.81
Sift
Uncertain
0.017
D;.
Sift4G
Uncertain
0.012
D;.
Polyphen
1.0
D;.
Vest4
0.92
MVP
0.97
MPC
0.52
ClinPred
0.19
T
GERP RS
5.0
Varity_R
0.20
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs62645958; hg19: chr1-94578618; COSMIC: COSV64670948; API