13-51941080-C-A

Variant names:

• chr13-51941080-C-A
• rs184388696
• NM_000053.4:c.3556+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000053.4(ATP7B):​c.3556+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP7B NM_000053.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.86
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Wilson disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.032742154 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-51941080-C-A is Pathogenic according to our data. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941080-C-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 495416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.3556+1G>T		splice_donor_variant, intron_variant	Intron 16 of 20	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.3556+1G>T		splice_donor_variant, intron_variant	Intron 16 of 20	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727240

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:4

Jul 18, 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.3556+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249588 control chromosomes (gnomAD). c.3556+1G>T has been reported in the literature in individuals affected with Wilson Disease (Karunas_2000, Khidiyatova_2008 proceedings of World Medical Conference, Balashova_2020, Couchonnal_2021). These data indicate that the variant is likely to be associated with disease. A variant involving the same nucleotide, c.3556+1G>A, has been classififed as likely pathgoenic by our lab. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both laboratories classified the variant as pathogenic (n=1) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

May 26, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 495416). Disruption of this splice site has been observed in individuals with Wilson disease (PMID: 7626145, 10994503, 26799313, 31708252; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 16 of the ATP7B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.9
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs184388696; hg19: chr13-52515216; COSMIC: COSV54435060; COSMIC: COSV54435060;