rs1484840087

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV001389182: Studies have shown that this variant alters ATP7B gene expression (PMID:10502776)." and additional evidence is available in ClinVar.

• 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, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001389182: Studies have shown that this variant alters ATP7B gene expression (PMID: 10502776).; SCV006080228: Published functional studies found this variant is associated with significantly reduced ATP7B protein expression (PMID: 10502776)
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406512.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	NM_001406512.1		c.-171_-157delTGGCCGAGACCGCGG		5_prime_UTR	Exon 1 of 22	NP_001393441.1	P35670-1
	ATP7B	NM_001406516.1		c.-171_-157delTGGCCGAGACCGCGG		5_prime_UTR	Exon 1 of 22	NP_001393445.1	P35670-4
	ATP7B	NM_001406522.1		c.-171_-157delTGGCCGAGACCGCGG		5_prime_UTR	Exon 1 of 22	NP_001393451.1	B7ZLR4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000911501.1		c.-171_-157delTGGCCGAGACCGCGG		5_prime_UTR	Exon 1 of 22	ENSP00000581560.1
	ATP7B	ENST00000873569.1		c.-436_-422delTGGCCGAGACCGCGG		5_prime_UTR	Exon 1 of 21	ENSP00000543628.1
	ATP7B	ENST00000713659.1		c.-436_-422delTGGCCGAGACCGCGG		5_prime_UTR	Exon 1 of 17	ENSP00000518961.1	A0AAQ5BGP2

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Wilson disease (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;