rs61753046
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000350.3(ABCA4):c.6658C>T(p.Gln2220Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000229 in 1,614,082 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
ABCA4
NM_000350.3 stop_gained
NM_000350.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 6.69
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 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 1-93997932-G-A is Pathogenic according to our data. Variant chr1-93997932-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-93997932-G-A is described in Lovd as [Pathogenic]. Variant chr1-93997932-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-93997932-G-A is described in Lovd as [Pathogenic]. Variant chr1-93997932-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.6658C>T | p.Gln2220Ter | stop_gained | 48/50 | ENST00000370225.4 | |
ABCA4 | XM_047416704.1 | c.6436C>T | p.Gln2146Ter | stop_gained | 47/49 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.6658C>T | p.Gln2220Ter | stop_gained | 48/50 | 1 | NM_000350.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152106Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
2
AN:
152106
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251408Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135886
GnomAD3 exomes
AF:
AC:
13
AN:
251408
Hom.:
AF XY:
AC XY:
10
AN XY:
135886
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 727224
GnomAD4 exome
AF:
AC:
35
AN:
1461858
Hom.:
Cov.:
31
AF XY:
AC XY:
26
AN XY:
727224
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74416
GnomAD4 genome
?
AF:
AC:
2
AN:
152224
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74416
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ExAC
?
AF:
AC:
6
Asia WGS
AF:
AC:
1
AN:
3478
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Severe early-childhood-onset retinal dystrophy Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Oct 13, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained c.6658C>T(p.Gln2220Ter) variant in ABCA4 gene has been reported in homozygous/compound heterozygous state in multiple patients affected with Retinal dystrophy or ABCA4 related disorders (Khan et. al., 2013; Maggi et. al., 2021; Shanks et. al., 2013). The p.Gln2220Ter variant has been observed in two affected male cousins in a family (Shanks et. al., 2013). The observed variant has been reported with alllele frequency of 0.005% in gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The nucleotide change c.6658C>T in ABCA4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Arcensus | Feb 01, 2013 | - - |
Retinitis pigmentosa 19 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Molecular Genetics, University of Zurich | Jan 30, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000099476, PMID:10958761). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000052, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 20, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 10958761, 25525159, 31429209, 34758253, 35456422, 22968130, 28341476, 28118664, 28041643, 32581362, 23134348) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change creates a premature translational stop signal (p.Gln2220*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs61753046, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with ABCA4-related retinal dystrophy (PMID: 22968130, 28041643, 28341476). ClinVar contains an entry for this variant (Variation ID: 99476). For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | Retina International | - | - - |
ABCA4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 04, 2023 | The ABCA4 c.6658C>T variant is predicted to result in premature protein termination (p.Gln2220*). This variant has been reported as causative for autosomal recessive ABCA4-related retinal disorders (see for example Khan et al. 2012. PubMed ID: 23134348; Shanks et al. 2013. PubMed ID: 22968130; Supplement in Holtan et al. 2020. PubMed ID: 31429209). This variant is reported in 0.042% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94463488-G-A). Nonsense variants in ABCA4 are expected to be pathogenic. Given all the evidence, we interpret c.6658C>T (p.Gln2220*) as pathogenic. - |
Cone dystrophy Pathogenic:1
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at