rs786204629

Variant names:

• chr13-51939095-TCAGAAC-T
• rs781266802
• NM_000053.4:c.3649_3654delGTTCTG

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM4 PP3 PP5_Very_Strong

The NM_000053.4(ATP7B):​c.3649_3654delGTTCTG​(p.Val1217_Leu1218del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ATP7B NM_000053.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.27

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000053.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 13-51939095-TCAGAAC-T is Pathogenic according to our data. Variant chr13-51939095-TCAGAAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189015.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.3649_3654delGTTCTG	p.Val1217_Leu1218del	conservative_inframe_deletion	Exon 17 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.3649_3654delGTTCTG	p.Val1217_Leu1218del	conservative_inframe_deletion	Exon 17 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 33

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: 0.0000361 AC: 9 AN: 249600 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461894 Hom.: 0 AF XY: 0.0000220 AC XY: 16 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:7

Aug 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jul 25, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.3649_3654del, results in the deletion of 2 amino acid(s) of the ATP7B protein (p.Val1217_Leu1218del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs781266802, gnomAD 0.02%). This variant has been observed in individual(s) with Wilson disease (PMID: 8980283, 9482578, 17154398, 17272994, 19118915). This variant is also known as 3648del6. ClinVar contains an entry for this variant (Variation ID: 189015). For these reasons, this variant has been classified as Pathogenic. -

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an in-frame deletion of two amino acids (p.Val1217_Leu1218del) in exon 17 of the ATP7B protein. This variant is also known as 3648del6 in the literature. Although functional studies have not been reported, this variant disrupts two conserved amino acids in the Phosphorylation (P) domain (a.a. 1004-1031, 1197-1312) of the ATP7B protein that is involved in the ATP hydrolysis, a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). This variant has been reported in over 15 individuals affected with Wilson disease (PMID: 7626145, 8980283, 9482578, 16207219, 16234011, 17154398, 17272994, 19118915, 19596473, 20082719, 22677543, 25014046, 31708252, 34400371). In several of these individuals, this variant was reported in the compound heterozygous state and homozygous state (PMID: 9482578, 17272994, 19118915). This variant has been identified in 9/249600 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jun 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 11, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.3649_3654delGTTCTG; p.Val1217_Leu1218del variant (rs781266802) also known as 3648del6, is reported in the literature in the compound heterozygous state in multiple individuals affected with Wilson's disease (Ferenci 2005, Folhoffer 2007, Kalinsky 1998, Kemppainen 1997, Loudianos 1998, Petrasek 2007, Thomas 1995, Todorov 2005, Vrabelova 2005, Wright 2009). This variant deletes two amino acid residues leaving the rest of the protein in-frame. This variant is reported in ClinVar (Variation ID: 189015), and is found in the Finnish European population with an allele frequency of 0.014% (3/21,562 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Ferenci P et al. Diagnostic value of quantitative hepatic copper determination in patients with Wilson's Disease. Clin Gastroenterol Hepatol. 2005 Aug;3(8):811-8. Folhoffer A et al. Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease. Eur J Gastroenterol Hepatol. 2007 Feb;19(2):105-11. Kalinsky H et al. Novel ATP7B mutations causing Wilson disease in several Israeli ethnic groups. Hum Mutat. 1998;11(2):145-51. Kemppainen R et al. A homozygous nonsense mutation and a combination of two mutations of the Wilson disease gene in patients with different lysyl oxidase activities in cultured fibroblasts. J Invest Dermatol. 1997 Jan;108(1):35-9. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. Petrasek J et al. Revised King's College score for liver transplantation in adult patients with Wilson's disease. Liver Transpl. 2007 Jan;13(1):55-61. Thomas GR et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995 Feb;9(2):210-7. Todorov T et al. Spectrum of mutations in the Wilson disease gene (ATP7B) in the Bulgarian population. Clin Genet. 2005 Nov;68(5):474-6. Vrabelova S et al. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol Genet Metab. 2005 Sep-Oct;86(1-2):277-85. Wright LM et al. Hepatocyte GP73 expression in Wilson disease. J Hepatol. 2009 Sep;51(3):557-64. -

not provided Pathogenic:2

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP7B: PM3:Strong, PM1, PM2, PM4 -

Mar 28, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM2, PM3_strong, PM4, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs781266802; hg19: chr13-52513231;