chr13-51961849-A-C

Variant names:

• chr13-51961849-A-C
• rs121907998
• NM_000053.4:c.1934T>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 PP2 PP5_Very_Strong

The NM_000053.4(ATP7B):​c.1934T>G​(p.Met645Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000384672: Functional studies in Sf9 cells demonstrated that the variant displayed copper uptake activity that was indistinguishable from wild type, however the variant was hyperphosphorylated compared to wild type ATP7B (Huster et al. 2012). Studies in SV40-transformed ATP7A-null cells also showed that the p.Met645Arg variant and other missense variants do not disrupt copper transport activity (Braiterman et al. 2014)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M645V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 2.49
• Publications: 40 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000384672: Functional studies in Sf9 cells demonstrated that the variant displayed copper uptake activity that was indistinguishable from wild type, however the variant was hyperphosphorylated compared to wild type ATP7B (Huster et al. 2012). Studies in SV40-transformed ATP7A-null cells also showed that the p.Met645Arg variant and other missense variants do not disrupt copper transport activity (Braiterman et al. 2014).; SCV000803476: Exon 6 skipping results in frameshift and stop gain, and reduced protein expression. PubMed:32284880; SCV001159371: Functional studies show the variant protein becomes hyperphosphorylated but otherwise has similar copper uptake activity as wild type ATP7B protein (Braiterman 2014, Huster 2012); PMID: 24706876, PMID: 22240481; SCV001194140: Functional assessments of this variant are available in the literature (PMID: 24706876).; SCV004362493: "This variant has shown to cause almost complete, out-of-frame skipping of exon 6 in mini-gene RNA assays using four different cell lines (PMID: 32284880). In compound heterozygous or homozygous HepG2 cell lines that were edited for this c.1934T>C variant using CRISPR/Cas9 technology, the amount of full length transcript was reduced by more than 70%, consistent with significantly reduced ATP7B protein expression in these cells (PMID: 32284880)."; SCV004822747: "In compound heterozygous or homozygous HepG2 cell lines that were edited for this c.1934T>C variant using CRISPR/Cas9 technology, the amount of full length transcript was reduced by more than 70%, consistent with significantly reduced ATP7B protein expression in these cells (PMID: 32284880)."; SCV001796090: Published functional studies demonstrate nearly complete exon-skipping when the variant was transfected into different cell lines (Merico et al., 2019); PMID: 32043565, 31980526, 32067425, 32284880, 32154060, 15952988, 27285482, 27437191, 17919502, 27398169, 25525159, 27415407, 28856630, 9311736, 24706876, 28433111, 22692182, 23962630, 22240481, 24253677, 29482223; SCV002720781: Minigene analysis of this variant in four cell lines demonstrated that this variant results in increased exon skipping compared to wildtype, with Hep2G cells compound heterozygous for this mutation expressing 15% of wild type levels and homozygous cells expressing approximately 30% (Merico, 2020).; SCV004104098: "One study observed a decrease in copper transport in lymphoblast cell lines from patients homozygous for c.1934T>G (Shah et al. 1997. PubMed ID: 9311736)."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_000053.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.
• PP5: Variant 13-51961849-A-C is Pathogenic according to our data. Variant chr13-51961849-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3862.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.1934T>G	p.Met645Arg	missense	Exon 6 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.1934T>G	p.Met645Arg	missense	Exon 7 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.1934T>G	p.Met645Arg	missense	Exon 7 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.1934T>G	p.Met645Arg	missense	Exon 6 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.1934T>G	p.Met645Arg	missense	Exon 6 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.1934T>G	p.Met645Arg	missense	Exon 6 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.000517 AC: 129 AN: 249580 AF XY: 0.000487

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.000203 AC: 296 AN: 1461584 Hom.: 0 Cov.: 31 AF XY: 0.000193 AC XY: 140 AN XY: 727102

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.00237 AC: 106 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.0000944 AC: 105 AN: 1111766

Other (OTH) AF: 0.000431 AC: 26 AN: 60376

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74432

African (AFR) AF: 0.0000241 AC: 1 AN: 41530

American (AMR) AF: 0.00255 AC: 39 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68022

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.000314 Hom.: 0

Bravo AF: 0.000518

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000485 AC: 4

ExAC AF: 0.000505 AC: 61

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
18	-	-	Wilson disease (18)
3	-	-	not provided (3)
1	-	-	ATP7B-related disorder (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-1.2	N
PhyloP100		2.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.43	N
REVEL	Uncertain	0.48
Sift	Benign	0.58	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.33
MVP		0.88
MPC		0.086
ClinPred		0.028	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.66
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: -12

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

Other links and lift over

dbSNP: rs121907998; hg19: chr13-52535985;