NM_000053.4:c.3045G>A
Variant summary
Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2
The NM_000053.4(ATP7B):c.3045G>A(p.Leu1015Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 1,592,588 control chromosomes in the GnomAD database, including 1,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1015L) has been classified as Likely benign.
Frequency
Consequence
NM_000053.4 synonymous
Scores
Clinical Significance
Conservation
Publications
- Wilson diseaseInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Benign. The variant received -12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATP7B | NM_000053.4 | c.3045G>A | p.Leu1015Leu | synonymous_variant | Exon 13 of 21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.0255 AC: 3881AN: 152250Hom.: 75 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0254 AC: 5471AN: 215302 AF XY: 0.0256 show subpopulations
GnomAD4 exome AF: 0.0353 AC: 50859AN: 1440220Hom.: 1029 Cov.: 31 AF XY: 0.0345 AC XY: 24665AN XY: 714636 show subpopulations
Age Distribution
GnomAD4 genome 0.0255 AC: 3878AN: 152368Hom.: 74 Cov.: 33 AF XY: 0.0246 AC XY: 1835AN XY: 74522 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:1Uncertain:3Benign:9
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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Criteria applied: PVS1_MOD; Identified as compund heterozygous with NM_000053.4:c.1934T>G -
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The c.3045G>A variant is predicted to encode a synonymous change (p.Leu1015Leu) in exon 13 of ATP7B. The prevalence of this variant in the gnomAD database (MAF=0.02544, 126 homozygotes) suggests that it is far too common to cause disease in homozygous state. However, we identified this variant in compound-heterozygous state with a well-established pathogenic truncating variant (p.Arg1319*). Research RNA-seq of proband liver tissue established that the p.Leu1015Leu variant causes exon 13 skipping in approximately 1/3 of transcripts. We propose that this variant is a hypomorphic allele that only causes disease when compound-heterozygous with a loss-of-function variant. We therefore interpret the p.Leu1015Leu variant as likely pathogenic. -
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not specified Benign:8
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Variant summary: ATP7B c.3045G>A alters a conserved nucleotide resulting in a synonymous change. At least one computational tool predicts no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.025 in 218250 control chromosomes in the gnomAD database, including 112 homozygotes. The observed variant frequency is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP7B causing Wilson Disease phenotype (0.0054), strongly suggesting that the variant is benign. c.3045G>A has been reported in the literature in individuals affected with Wilson Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Wilson Disease.Nine 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 consensus of benign (benign/likely benign n=7, likely pathogenic n=1, VUS n=1) . Based on the evidence outlined above, the variant was classified as benign. -
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Inborn genetic diseases Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at