rs369488210

chr13-52011283-T-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000053.4(ATP7B):c.51+4A>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,052 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ATP7B NM_000053.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 2.89

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-52011283-T-A is Pathogenic according to our data. Variant chr13-52011283-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 312401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-52011283-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.51+4A>T		splice_donor_region_variant, intron_variant		ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.51+4A>T		splice_donor_region_variant, intron_variant		1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249336 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135308

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461844 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:15

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 14, 2023	The ATP7B c.51+4A>T variant (rs369488210) is reported in the literature in numerous individuals with Wilson disease who were either compound heterozygous with another pathogenic variant or homozygous for c.51+4A>T (Arruda 2014, Couchonnal 2021, Garcia-Villarreal 2021, Lovicu 2009, Sanchez-Monteagudo 2020). This variant is also reported in ClinVar (Variation ID: 312401). This variant is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 1, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Arruda WO et al. Pathogenic compound heterozygous ATP7B mutations with hypoceruloplasminaemia without clinical features of Wilson's disease. J Clin Neurosci. 2014 Feb;21(2):335-6. PMID: 23962630. Couchonnal E et al. ATP7B variant spectrum in a French pediatric Wilson disease cohort. Eur J Med Genet. 2021 Oct;64(10):104305. PMID: 34400371. Garcia-Villarreal L et al. Wilson disease: revision of diagnostic criteria in a clinical series with great genetic homogeneity. J Gastroenterol. 2021 Jan;56(1):78-89. PMID: 33159804. Lovicu M et al. RNA analysis of consensus sequence splicing mutations: implications for the diagnosis of Wilson disease. Genet Test Mol Biomarkers. 2009 Apr;13(2):185-91. PMID: 19371217. Sanchez-Monteagudo A et al. Genetics of Wilson disease and Wilson-like phenotype in a clinical series from eastern Spain. Clin Genet. 2020 May;97(5):758-763. PMID: 32043565. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The ATP7B c.51+4A>T splice-region variant has been described in eight studies in which it was found in a total of 11 patients with Wilson disease including in three in a homozygous state (including two siblings) and in 11 in a compound heterozygous state (including two pairs of siblings) (Deguti et al. 2004; Lovicu et al. 2009; Nicastro et al. 2009; Nicastro et al. 2010; Bost et al. 2012; Bem et al. 2013; Arruda et al. 2014; Paradisi et al. 2014). The c.51+4A>T variant was absent from 108 controls but is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. One functional study demonstrated that the c.51+4A>T variant did not result in aberrant splicing (Deguti et al. 2004). Lovicu et al. (2004) however showed that the variant resulted in aberrant splicing in individuals who were homozygous for the variant but not in compound heterozygotes (Lovicu et al. 2009). Based on the collective evidence, the c.51+4A>T variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant causes an A to T nucleotide substitution at the +4 position of intron 1 of the ATP7B gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 15024742, 19118915, 19371217, 23518715, 23962630, 25497208), indicating that this variant contributes to disease. It has been reported in the homozygous state in two siblings (PMID: 15024742) and compound heterozygous state in at least eight individuals from different families (PMID: 19118915, 19371217, 23518715, 23962630, 25497208). This variant has been identified in 4/249336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2020	Variant summary: ATP7B c.51+4A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports splicing assay performed on the patients blood sample showed partial splicing defect (Lovicu_2009). The variant allele was found at a frequency of 1.6e-05 in 249536 control chromosomes (gnomAD and publication data). c.51+4A>T has been reported in the literature in the compound heterozygous or homozygous state in multiple individuals affected with Wilson Disease (Deguti_2004, Margarit_2005, Lovicu_2009, Coffey_2013, Paradisi_2014). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2019	The c.51+4A>T variant in ATP7B has been reported in the homozygous or compound heterozygous state in at least 5 individuals with clinical and/or biochemical features of Wilson disease, and segregated with disease in at least 1 affected relative (Deguti 2004, Lovicu 2009, Bem 2013, Paradisi 2014). It has also been identified in 0.003% (1/34528) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported as likely pathogenic in ClinVar (Variation ID 312401). This variant is located in the 5' splice region. Computational tools predict a weak splicing impact, though this information is not predictive enough to determine pathogenicity. Furthermore, RNA analyses performed on individuals carrying this variant have produced conflicting results regarding its impact on splicing (Deguti 2004, Lovicu 2009). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease based on its identification in multiple affected individuals and low frequency in controls. ACMG/AMP Criteria applied: PM3_Strong, PM2, PP1. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	This sequence change falls in intron 1 of the ATP7B gene. It does not directly change the encoded amino acid sequence of the ATP7B protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs369488210, gnomAD 0.003%). This variant has been observed in individuals with ATP7B-related conditions (PMID: 15024742, 19371217, 20967755, 23962630, 25497208). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 312401). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the insertion of 369 nucleotides from intron 1 and introduces a premature termination codon (PMID: 19371217). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 15, 2023	PP1, PP3, PP4, PM2, PM3, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
Cadd	Benign	21
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.76		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs369488210; hg19: chr13-52585419;