chr1-94005470-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000350.3(ABCA4):c.6118C>T(p.Arg2040Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,982 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
NM_000350.3 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 | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.6118C>T | p.Arg2040Ter | stop_gained | 44/50 | ENST00000370225.4 | |
ABCA4 | XM_047416704.1 | c.5896C>T | p.Arg1966Ter | stop_gained | 43/49 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.6118C>T | p.Arg2040Ter | stop_gained | 44/50 | 1 | NM_000350.3 | P1 | |
ABCA4 | ENST00000465352.1 | n.534C>T | non_coding_transcript_exon_variant | 5/6 | 5 | ||||
ABCA4 | ENST00000484388.1 | n.232C>T | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152112Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251316Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135802
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461870Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 727230
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152112Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74296
ClinVar
Submissions by phenotype
not provided Pathogenic:3Other:1
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 16, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2023 | This sequence change creates a premature translational stop signal (p.Arg2040*) 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 (rs61753038, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with ABCA4-related retinal dystrophy (PMID: 26161775, 29555955, 29925512; Invitae). ClinVar contains an entry for this variant (Variation ID: 99431). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2018 | The R2040X nonsense variant in the ABCA4 gene has been reported in association with Stargardt disease (Baum et al., 2003; Downes et al., 2012; Fujinami et al., 2013; Jiang et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R2040X variant was observed in 3/18866 (0.016%) alleles in East Asian individuals in large population databases (Lek et al., 2016). We interpret R2040X as a pathogenic variant. - |
Severe early-childhood-onset retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Stop-gained (nonsense) is 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. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000099431 / PMID: 12592048 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 15, 2018 | - - |
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 submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Stargardt disease Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at