chr1-94007731-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 5P and 8B. PM1PM5PP3BP4_StrongBS2
The NM_000350.3(ABCA4):c.5908C>T(p.Leu1970Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00479 in 1,613,956 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1970I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000350.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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ABCA4 | ENST00000370225.4 | c.5908C>T | p.Leu1970Phe | missense_variant | Exon 43 of 50 | 1 | NM_000350.3 | ENSP00000359245.3 | ||
ABCA4 | ENST00000465352.1 | n.324C>T | non_coding_transcript_exon_variant | Exon 4 of 6 | 5 | |||||
ABCA4 | ENST00000484388.1 | n.22C>T | non_coding_transcript_exon_variant | Exon 1 of 2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00354 AC: 538AN: 152142Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00300 AC: 751AN: 250638Hom.: 2 AF XY: 0.00308 AC XY: 418AN XY: 135618
GnomAD4 exome AF: 0.00492 AC: 7186AN: 1461696Hom.: 24 Cov.: 31 AF XY: 0.00474 AC XY: 3443AN XY: 727136
GnomAD4 genome AF: 0.00353 AC: 538AN: 152260Hom.: 1 Cov.: 32 AF XY: 0.00337 AC XY: 251AN XY: 74462
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3Other:1
ABCA4: PM5:Supporting, PP3, BS2 -
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This variant is associated with the following publications: (PMID: 9781034, 25087612, 9295268, 23953153, 9973280, 10958763, 12515255, 22264887, 28118664, 27408750, 28157192, 29925512, 30718709, 33633436) -
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Retinal dystrophy Uncertain:2
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Vitreoretinopathy Pathogenic:1
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Stargardt disease Pathogenic:1
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ABCA4-related disorder Uncertain:1
The ABCA4 c.5908C>T variant is predicted to result in the amino acid substitution p.Leu1970Phe. This variant has been reported many times in individuals with Stargardt disease, late-onset fundus flavimaculatus, and/or age-related macular degeneration (Lewis et al. 1999. PubMed ID: 9973280; Allikmets et al. 1997. PubMed ID: 9295268; Rozet et al. 1998. PubMed ID: 9781034; Webster et al. 2001. PubMed ID: 11328725; Thiadens et al. 2012. PubMed ID: 22264887; Fujinami et al. 2019. PubMed ID: 29925512). However, in some of these cases a second causative variant in ABCA4 was not detected. Additionally, this variant has been reported in individuals in which there were pathogenic variants in different genes that could explain their inherited retinal dystrophy (Jespersgaard et al. 2019. PubMed ID: 30718709; Zhu et al. 2022. PubMed ID: 35456422). Here, at PreventionGenetics, we have also detected this variant in the absence of a second causative variant, and sometimes these individuals were positive for pathogenic variants in different genes (Internal Data). This variant is documented in 0.46% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including three homozygotes (http://gnomad.broadinstitute.org/variant/1-94473287-G-A). Given the conflicting evidence, the clinical significance of this variant is uncertain at this time. -
Severe early-childhood-onset retinal dystrophy Uncertain:1
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not specified Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at