rs145961131
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The ENST00000370225.4(ABCA4):c.1906C>T(p.Gln636Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,614,022 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000370225.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.1906C>T | p.Gln636Ter | stop_gained | 13/50 | ENST00000370225.4 | NP_000341.2 | |
ABCA4 | XM_047416704.1 | c.1906C>T | p.Gln636Ter | stop_gained | 13/49 | XP_047272660.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.1906C>T | p.Gln636Ter | stop_gained | 13/50 | 1 | NM_000350.3 | ENSP00000359245 | P1 | |
ABCA4 | ENST00000649773.1 | c.1906C>T | p.Gln636Ter | stop_gained | 13/19 | ENSP00000496882 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251126Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135704
GnomAD4 exome AF: 0.000101 AC: 147AN: 1461864Hom.: 0 Cov.: 37 AF XY: 0.0000949 AC XY: 69AN XY: 727232
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74324
ClinVar
Submissions by phenotype
Severe early-childhood-onset retinal dystrophy Pathogenic:2
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Nov 04, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2019 | 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: 29925512, 24020726, 29884405, 22968130, 21911583, 22863181, 28559085, 30204727) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 10, 2023 | This sequence change creates a premature translational stop signal (p.Gln636*) 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 (rs145961131, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with ABCA4-related disorders including Stargardt disease and retinitis pigmentosa (PMID: 21911583, 22968130, 28041643). ClinVar contains an entry for this variant (Variation ID: 265012). For these reasons, this variant has been classified as Pathogenic. - |
Retinitis pigmentosa 19 Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 25, 2023 | The heterozygous p.Gln636Ter variant in ABCA4 was identified by our study, in the compound heterozygous state with another pathogenic variant (ClinVar Variation ID: 99478). This individual also carried another pathogenic variant (ClinVar Variation ID: 99478); however, the phase of these variants is unknown at this time. The p.Gln636Ter variant in ABCA4 has been previously reported in 8 unrelated individuals with autosomal recessive ABCA4-related retinopathy (PMID: 24020726, PMID: 29884405, PMID: 22863181, PMID: 28559085, PMID: 30204727, PMID: 28041643, PMID: 22968130, PMID: 21911583), but has been identified in 0.004% (5/113446) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs145961131). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 8 previously reported individuals (PMID: 24020726, PMID: 29884405, PMID: 22863181, PMID: 28559085, PMID: 30204727, PMID: 28041643, PMID: 22968130, PMID: 21911583), 1 was a homozygote (PMID: 21911583), 6 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 24020726, ClinVar Variation ID: 92870; PMID: 29884405, ClinVar Variation ID: 7879; PMID: 28559085, ClinVar Variation ID: 7879; PMID: 30204727, ClinVar Variation ID: 99390; PMID: 28041643, ClinVar Variation ID: 30218; PMID: 22968130, ClinVar Variation ID: 99505) and 1 was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 22863181, ClinVar Variation ID: 7888), which increases the likelihood that the p.Gln636Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 265012) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 636, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCA4 gene is an established disease mechanism in autosomal recessive ABCA4-related retinopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ABCA4-related retinopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_VeryStrong (Richards 2015). - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Oct 12, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at