chr13-51949716-CA-C

Variant names:

• chr13-51949716-CA-C
• rs1057516643
• NM_000053.4:c.2810delT

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PVS1 PS3 PM2 PP3 PP5_Very_Strong

The NM_000053.4(ATP7B):​c.2810delT​(p.Val937GlyfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001339143: In copper resistance assay to determine the effect of the mutation on cell survival, the variant completely inhibited copper-transporting activity as indicated by the rapid death of cells expressing the mutant ATP7B when they were exposed to 20uM copper (Wan_2010)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V937V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP7B NM_000053.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.96
• Publications: 9 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 23 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001339143: In copper resistance assay to determine the effect of the mutation on cell survival, the variant completely inhibited copper-transporting activity as indicated by the rapid death of cells expressing the mutant ATP7B when they were exposed to 20uM copper (Wan_2010).; SCV000568296: Expression studies found that c.2810delT completely inhibited copper-transporting activity of the ATP7B protein (Wan et al., 2010).; SCV002749246: The authors of this functional study showed that this mutation is unable to produce functional ATP7B protein and completely inhibits copper-transporting activity. However, this alteration also results in the expression of alternative in frame splice variants that retain copper transporting activity at a significantly higher level than wild type protein, which, authors propose, are responsible for this individuals attenuated phenotype (Wan L, et al. Hepatology 2010;52(5):1662-70).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-51949716-CA-C is Pathogenic according to our data. Variant chr13-51949716-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 370632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000053.4. 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_000053.4	MANE Select	c.2810delT	p.Val937GlyfsTer5	frameshift	Exon 12 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.2810delT	p.Val937GlyfsTer5	frameshift	Exon 13 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.2810delT	p.Val937GlyfsTer5	frameshift	Exon 13 of 22	NP_001393441.1	P35670-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.2810delT	p.Val937GlyfsTer5	frameshift	Exon 12 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.2666delT	p.Val889GlyfsTer5	frameshift	Exon 12 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.2810delT	p.Val937GlyfsTer5	frameshift	Exon 12 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249370 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

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: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Wilson disease (5)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: 0

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

Other links and lift over

dbSNP: rs1057516643; hg19: chr13-52523852;