rs776572343
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_000053.4(ATP7B):c.2355+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000053.4 splice_region, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.2355+4A>G | splice_region_variant, intron_variant | Intron 8 of 20 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249180Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135244
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461786Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727198
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:2Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 24, 2023 | This variant causes an A to G nucleotide substitution at the +4 position of intron 8 of the ATP7B gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATP7B-related disorders in the literature. This variant has been identified in 1/249180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 24, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 08, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 26, 2024 | The ATP7B c.2355+4A>G variant (rs776572343) is reported in the literature in an individual affected with a diagnosis or suspicion of Wilson disease, although it is unclear if this individual carried additional variants in ATP7B (Davies 2008). The c.2355+4A>G variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, given the lack of clinical and functional data, the significance of the c.2355+4A>G variant is uncertain at this time. References: Davies LP et al. New mutations in the Wilson disease gene, ATP7B: implications for molecular testing. Genet Test. 2008 Mar;12(1):139-45. PMID: 18373411. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 22, 2022 | This variant has been observed in individual(s) with Wilson disease (PMID: 18373411; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 551811). This variant is present in population databases (rs776572343, gnomAD 0.003%). This sequence change falls in intron 8 of the ATP7B gene. It does not directly change the encoded amino acid sequence of the ATP7B protein. It affects a nucleotide within the consensus splice site. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 08, 2016 | The c.2355+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 8 in the ATP7B gene. This variant was identified in one individual with biochemical testing suggestive of a diagnosis of Wilson disease; however, additional genotype and phenotype information were not provided (Davies LP, Genet. Test. 2008 Mar; 12(1):139-45). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6109 samples (12218 alleles) with coverage at this position. This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at