rs1021025464

Positions:

• chr13-52012013-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001406511.1(ATP7B):​c.-55+7A>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 0.000202 in 361,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: ATP7B NM_001406511.1 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 2.96

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ATP7B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-52012013-T-C is Pathogenic according to our data. Variant chr13-52012013-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393099.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=2}. Variant chr13-52012013-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_001406511.1	c.-55+7A>G		splice_region_variant, intron_variant			NP_001393440.1
ATP7B	NM_001406513.1	c.-55+7A>G		splice_region_variant, intron_variant			NP_001393442.1
ATP7B	NM_001406521.1	c.-55+7A>G		splice_region_variant, intron_variant			NP_001393450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000635406.1	n.106+7A>G		splice_region_variant, intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000272 AC: 57 AN: 209360 Hom.: 0 Cov.: 0 AF XY: 0.000348 AC XY: 39 AN XY: 111964

Gnomad4 AFR exome AF: 0.000172

Gnomad4 AMR exome AF: 0.000122

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00116

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.0000899

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74512

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000102

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 04, 2022	Variant summary: ATP7B c.-676A>G is located in the untranscribed region upstream of the ATP7B gene region. The variant allele was found at a frequency of 0.00016 in 31402 control chromosomes (gnomAD). c.-676A>G has been reported in the literature in multiple individuals affected with Wilson Disease (examples: Mukherjee_2014 and Lu_2014). These data indicate that the variant is very likely to be associated with disease. Functional analysis have demonstrated that c.-676A>G reduced promotor activity, however, this report does not allow convincing conclusions about the variant effect in vivo (Mukherjee_2014). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	in vitro;research	Gill Bejerano Lab, Stanford University	Mar 27, 2018	The variant chr13:g.52,586,149T>C (NC_000013.9), is positioned 676 bases upstream of the annotated canonical translation start site of ATP7B, in the proximal promoter. It was verified by Sanger sequencing to be heterozygous in both healthy parents and homozygous in the patient. It has also been observed as heterozygous in 5 East Asian individuals in the Genome Aggregation Database (Lek 2016). The variant chr13:g.52,586,149T>C has previously been observed in heterozygosity in one Chinese (Lu 2014) and ten Indian individuals with Wilson Disease (Mukherjee 2014). In these instances, chr13:g.52,586,149T>C was almost always identified in conjunction with one or more heterozygous ATP7B missense variants (with exceptions where no ATP7B coding variants were detected and yet only this promoter SNV was observed as heterozygous). In vitro studies indicate that chr13:g.52,586,149T>C reduces ATP7B promoter activity, likely through disruption of a metal regulatory transcription factor 1 (MTF1) binding site. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 29, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2023	This variant occurs in a non-coding region of the ATP7B gene. It does not change the encoded amino acid sequence of the ATP7B protein. This variant is present in population databases (no rsID available, gnomAD 0.3%). This variant has been observed in individual(s) with Wilson disease (PMID: 24094725, 30087448; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 393099). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ATP7B function (PMID: 24094725, 30087448). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2024	Functional analysis in one study found that c.-676 A>G was associated with some reduction in promotor activity, however the significance of this is unclear (PMID: 30087448, 24094725); This variant is associated with the following publications: (PMID: 24094725, 33971252, 30087448, 24878384) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 02, 2023	PM3, PS3, PS4_moderate -

ATP7B-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2024

The ATP7B c.-676A>G variant is located in the 5' untranslated region. This variant is also referred to as chr13:g.52,586,149T>C (NC_000013.10, hg19) in the literature. It has been reported in the homozygous state in two individuals with Wilson disease (Chen et al. 2018. PubMed ID: 30087448; Lu et al. 2014. PubMed ID: 24878384, Table 2, Patient WD001). However, one of these individuals harbored multiple additional variants in ATP7B (Lu et al. 2014. PubMed ID: 24878384, Table 2, Patient WD001). This variant has also been reported in additional individuals with Wilson Disease, however clinical details were not provided (Lu et al. 2014. PubMed ID: 24878384, Table 2;Mukherjee et al. 2014. PubMed ID: 24094725). Functional assessment using luciferase promoter-reporter assays indicate that this variant leads to a decrease in reporter expression (Mukherjee et al. 2014. PubMed ID: 24094725, Figure 2; Chen et al. 2018. PubMed ID: 30087448, Figure 2). This variant has been reported 5 times among ~31,000 alleles (~0.02%) in a large population database, and is interpreted as uncertain significance, likely pathogenic, and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/393099/). Based on these observations, the c.-676A>G variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.72

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1021025464; hg19: chr13-52586149;