rs1021025464

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 2.96

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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: {Likely_pathogenic=2, Uncertain_significance=1, 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	Effect	Exon rank	Protein
ATP7B	NM_001406511.1 link	c.-55+7A>G	splice_region_variant, intron_variant	Intron 1 of 21	NP_001393440.1
ATP7B	NM_001406513.1 link	c.-55+7A>G	splice_region_variant, intron_variant	Intron 1 of 21	NP_001393442.1
ATP7B	NM_001406521.1 link	c.-55+7A>G	splice_region_variant, intron_variant	Intron 1 of 21	NP_001393450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000635406.1 link	n.106+7A>G		splice_region_variant, intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

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:

AN:

209360

Hom.:

Cov.:

AF XY:

0.000348

AC XY:

AN XY:

111964

show subpopulations

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:

AN:

152372

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74512

show subpopulations

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:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:4

Mar 27, 2018

Gill Bejerano Lab, Stanford University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: in vitro;research

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. -

Jul 29, 2019

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 393099). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects ATP7B function (PMID: 24094725, 30087448). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. 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. This variant is present in population databases (no rsID available, gnomAD 0.3%). 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. -

Nov 04, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Pathogenic:1Uncertain:1

Dec 11, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Feb 02, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3, PS3, PS4_moderate -

ATP7B-related disorder

Pathogenic:1

May 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

DANN

Benign

0.72

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over