NM_000350.3:c.1411G>A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5BP4_StrongBS2
The NM_000350.3(ABCA4):c.1411G>A(p.Glu471Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000725 in 1,614,108 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. E471Q) has been classified as Pathogenic.
Frequency
Consequence
NM_000350.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.1411G>A | p.Glu471Lys | missense_variant | Exon 11 of 50 | ENST00000370225.4 | NP_000341.2 | |
ABCA4 | NM_001425324.1 | c.1411G>A | p.Glu471Lys | missense_variant | Exon 11 of 49 | NP_001412253.1 | ||
LOC124904222 | XR_007066231.1 | n.203-5896C>T | intron_variant | Intron 1 of 1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.1411G>A | p.Glu471Lys | missense_variant | Exon 11 of 50 | 1 | NM_000350.3 | ENSP00000359245.3 | ||
ABCA4 | ENST00000649773.1 | c.1411G>A | p.Glu471Lys | missense_variant | Exon 11 of 19 | ENSP00000496882.1 |
Frequencies
GnomAD3 genomes AF: 0.000880 AC: 134AN: 152226Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.000831 AC: 209AN: 251400Hom.: 0 AF XY: 0.000846 AC XY: 115AN XY: 135868
GnomAD4 exome AF: 0.000709 AC: 1037AN: 1461882Hom.: 1 Cov.: 31 AF XY: 0.000745 AC XY: 542AN XY: 727240
GnomAD4 genome AF: 0.000880 AC: 134AN: 152226Hom.: 2 Cov.: 32 AF XY: 0.000807 AC XY: 60AN XY: 74372
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2Other:1
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Published functional studies demonstrate no impact on ATP binding and hydrolysis (PMID: 11017087); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 9295268, 11919200, 10958763, 14971589, 9973280, 18977788, 27491360, 19230850, 19074458, 12796258, 16546111, 10090887, 12037008, 28446513, 9781034, 23953153, 35120629, 31456290, 31964843, 34321860, 11017087) -
ABCA4: BP4 -
Retinal dystrophy Uncertain:1Benign:1
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Stargardt disease Pathogenic:1
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Age related macular degeneration 2 Uncertain:1
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Inborn genetic diseases Uncertain:1
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Severe early-childhood-onset retinal dystrophy Uncertain:1
This variant was identified together with NM_000350.3:c.1622T>C, NM_000350.3:c.3113C>T, NM_000350.3:c.2588G>C and NM_000350.3:c.5693G>A. -
ABCA4-related disorder Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not specified Benign:1
Variant summary: ABCA4 c.1411G>A (p.Glu471Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 251400 control chromosomes in GnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.00083 vs 0.0014), allowing no conclusion about variant significance. c.1411G>A has been reported in the literature in individuals affected with Retinitis Pigmentosa or Stargardt disease, but the second pathogenic variant and the phase information are not always known (example: Allikmets_1997, Lewis_1999, Hanany_2020, Reinhard_2007, Sharon_2019). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (phase unknown with p.Gly863Ala and p.Asp1532Asn of ABCA4; in cis with c.4919G>A/p.Arg1640Gln of ABCA4), providing supporting evidence for a benign role (Fujinami_2013 and Mena_2021). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Sun_2000). The following publications have been ascertained in the context of this evaluation (PMID: 9295268, 23953153, 31964843, 33841504, 17562343, 10958763, 31456290, 11017087, 11328725). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS: 8, Likely pathognic: 1, Benign: 1) . Based on the evidence outlined above, the variant was classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at