rs1484840087

Variant names:

• chr13-52011758-TCCGCGGTCTCGGCCA-T
• rs1484840087
• NM_001406512.1:c.-171_-157delTGGCCGAGACCGCGG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001406512.1(ATP7B):​c.-171_-157delTGGCCGAGACCGCGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,356 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 34)
• Consequence: ATP7B NM_001406512.1 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.33
• Publications: 1 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: Likely_pathogenic. The variant received 8 ACMG points.

• PP5: Variant 13-52011758-TCCGCGGTCTCGGCCA-T is Pathogenic according to our data. Variant chr13-52011758-TCCGCGGTCTCGGCCA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 555936.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_001406512.1	c.-171_-157delTGGCCGAGACCGCGG		5_prime_UTR_variant	Exon 1 of 22		NP_001393441.1
ATP7B	NM_001406516.1	c.-171_-157delTGGCCGAGACCGCGG		5_prime_UTR_variant	Exon 1 of 22		NP_001393445.1
ATP7B	NM_001406522.1	c.-171_-157delTGGCCGAGACCGCGG		5_prime_UTR_variant	Exon 1 of 22		NP_001393451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000713659.1	c.-436_-422delTGGCCGAGACCGCGG		5_prime_UTR_variant	Exon 1 of 17			ENSP00000518961.1
ATP7B	ENST00000635406.1	n.106+247_106+261delTGGCCGAGACCGCGG		intron_variant	Intron 1 of 3	4
ATP7B	ENST00000448424.7	c.-436_-422delTGGCCGAGACCGCGG		upstream_gene_variant		1		ENSP00000416738.3
ATP7B	ENST00000673864.2	n.-436_-422delTGGCCGAGACCGCGG		upstream_gene_variant				ENSP00000501045.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152238 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: 0.0000441

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152356 Hom.: 0 Cov.: 34 AF XY: 0.0000268 AC XY: 2 AN XY: 74502

African (AFR) AF: 0.00 AC: 0 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:4

Nov 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 21, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2018

Counsyl

Significance: 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. -

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Wilson disease (PMID: 10502776, 14616767, 26752957). ClinVar contains an entry for this variant (Variation ID: 555936). Studies have shown that this variant alters ATP7B gene expression (PMID: 10502776). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Nov 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found this variant is associated with significantly reduced ATP7B protein expression (PMID: 10502776); No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 26752957, 10502776, 18728530, 14616767, 36096368, 33159804) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

Splicing

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

Other links and lift over

dbSNP: rs1484840087; hg19: chr13-52585894;