NM_000053.4:c.3809A>G

Variant names:

• chr13-51937570-T-C
• rs121907990
• NM_000053.4:c.3809A>G

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):​c.3809A>G​(p.Asn1270Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,614,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000626859: Experimental studies have shown that this missense change affects ATP7B function (PMID:9654149, 22240481)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1270I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23 U:1
• Conservation: PhyloP100: 7.97
• Publications: 72 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 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000626859: Experimental studies have shown that this missense change affects ATP7B function (PMID: 9654149, 22240481).; SCV000918603: c.3809A>G has been reported in the literature in numerous individuals affected with Wilson Disease as both a homozygous and compound heterozygous allele. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence on the variant and showed that copper uptake and transport are both defective (Huster_2012).; SCV001157792: Biochemical analyses indicate this variant has severely reduced copper transport activity (Huster 2012), and it fails to rescue growth defects of mutant yeast to the extent of wildtype protein (Iida 1998). PMID: 22240481 PMID: 26207219; SCV004847782: In vitro functional studies suggest that the variant may impact protein function (Huster 2012, Lida 1998); SCV005431198: Functional studies in Chinese hamster ovary cells have shown the mutant protein to exhibit significantly reduced copper uptake and transport, and increased phosphorylation relative to wild type (PMID: 22240481). In a separate study, this variant was unable to rescue function in a knockout ccc2 yeast model (PMID: 9654149).; SCV006061524: Functional studies in Chinese hamster ovary cells have shown the mutant protein to exhibit significantly reduced copper uptake and transport, and increased phosphorylation relative to wild type (PMID: 22240481). In a separate study, this variant was unable to rescue function in a knockout ccc2 yeast model (PMID: 9654149).; SCV006077091: Functional studies indicate that this variant demonstrates impaired chloride transport and hyperphosphorylation and affects copper transport, supporting a damaging effect (Iida et al., 1998; Huster et al., 2012).; SCV002558357: Published functional studies indicate that this variant leads to hyperphosphorylation and affects copper transport, supporting a damaging effect (Iida et al., 1998; Huster et al., 2012);; SCV002620184: When expressed in Sf9 cells, this mutation demonstrated impaired chloride transport and hyperphosphorylation (Huster D et al. Gastroenterology, 2012 Apr;142:947-956.e5).; SCV004726765: Functional studies suggest that this variant alters normal protein function (Table S1, Schushan et al. 2012. PubMed ID: 22692182).
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000053.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51937570-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1685251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 13-51937570-T-C is Pathogenic according to our data. Variant chr13-51937570-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3859.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.3809A>G	p.Asn1270Ser	missense	Exon 18 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.3809A>G	p.Asn1270Ser	missense	Exon 19 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.3809A>G	p.Asn1270Ser	missense	Exon 19 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.3809A>G	p.Asn1270Ser	missense	Exon 18 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.3665A>G	p.Asn1222Ser	missense	Exon 18 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.3614A>G	p.Asn1205Ser	missense	Exon 17 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000216 AC: 54 AN: 249580 AF XY: 0.000244

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000222

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000120 AC: 176 AN: 1461886 Hom.: 1 Cov.: 35 AF XY: 0.000131 AC XY: 95 AN XY: 727246

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000980 AC: 109 AN: 1112012

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.000551 AC XY: 41 AN XY: 74378

African (AFR) AF: 0.0000723 AC: 3 AN: 41474

American (AMR) AF: 0.00308 AC: 47 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000110 Hom.: 0

Bravo AF: 0.000298

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000483 AC: 2

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000149 AC: 18

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	1	-	Wilson disease (18)
4	-	-	not provided (4)
1	-	-	ATP7B-related disorder (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		8.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		1.0
MPC		0.34
ClinPred		0.62	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.91
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121907990; hg19: chr13-52511706;