chr13-51942395-CG-C

Variant names:

• chr13-51942395-CG-C
• rs137853281
• NM_000053.4:c.3402delC

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000053.4(ATP7B):​c.3402delC​(p.Ala1135GlnfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000431 in 1,461,814 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: "SCV001361701: At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated subcellular mislocalization (Huster_2003)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P1134P) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: ATP7B NM_000053.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: -0.448
• Publications: 41 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 22 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: SCV001361701: At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated subcellular mislocalization (Huster_2003).; SCV004845365: Functional studies have shown that this variant disrupts intracellular localization (PMID: 12557139).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-51942395-CG-C is Pathogenic according to our data. Variant chr13-51942395-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 88958.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.3402delC	p.Ala1135GlnfsTer13	frameshift	Exon 15 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.3402delC	p.Ala1135GlnfsTer13	frameshift	Exon 16 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.3402delC	p.Ala1135GlnfsTer13	frameshift	Exon 16 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.3402delC	p.Ala1135GlnfsTer13	frameshift	Exon 15 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.3258delC	p.Ala1087GlnfsTer13	frameshift	Exon 15 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.3207delC	p.Ala1070GlnfsTer13	frameshift	Exon 14 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000642 AC: 16 AN: 249374 AF XY: 0.0000739

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461814 Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29 AN XY: 727212

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

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 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: 0.0000531 AC: 59 AN: 1112008

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000542 Hom.: 0

Bravo AF: 0.0000416

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Wilson disease (16)
5	-	-	not provided (5)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.45
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137853281; hg19: chr13-52516531;