rs199821556

Positions:

• chr13-51937493-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_000053.4(ATP7B):​c.3886G>A​(p.Asp1296Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000154 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1296G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:6
• Conservation: PhyloP100: 6.13

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51937492-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 802993.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP5: Variant 13-51937493-C-T is Pathogenic according to our data. Variant chr13-51937493-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161207.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=5, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.3886G>A	p.Asp1296Asn	missense_variant	18/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3886G>A	p.Asp1296Asn	missense_variant	18/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000200 AC: 50 AN: 249436 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 135332

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 222 AN: 1461708 Hom.: 0 Cov.: 35 AF XY: 0.000140 AC XY: 102 AN XY: 727140

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00292

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00146

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74482

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000234 AC: 1

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Pathogenic:4 Uncertain:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2023	Variant summary: ATP7B c.3886G>A (p.Asp1296Asn) results in a conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 249436 control chromosomes (i.e. 50 / 249436 alleles) in the gnomAD database. This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0054), allowing no conclusion about variant significance. c.3886G>A has been reported in the literature in multiple individuals affected with Wilson Disease, including at least three homozygotes (Knuutinen_2021, Sipila_2020) and several compound heterozygous patients diagnosed in the presymptomatic stage (e.g. Ohya_2002, Owada_2002, Nakayama_2008, Lee_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 18, 2018	The ATP7B c.3886G>A (p.Asp1296Asn) variant is a missense variant that has been reported in at least two studies and is found in a compound heterozygous state in three individuals from two families, including two brothers, with presymptomatic Wilson disease (Ohya et al. 2002; Nakayama et al. 2008). In each family an unaffected parent was heterozygous for the p.Asp1296Asn variant. This variant was reported in one of 50 controls and is reported at a frequency of 0.001815 in the European (Finnish) population of the Exome Aggregation Consortium (Lin et al. 2010). The evidence for this variant is limited. The p.Asp1296Asn variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces aspartic acid with asparagine at codon 1296 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in the homozygous state in individuals affected with Wilson disease (PMID: 32618023, 33948933) and in the compound heterozygous state in individuals presymptomatic for Wilson disease (PMID: 11954751, 12032531, 18424137). This variant has been detected in an individual with cancer (PMID: 20045993) and in unaffected populations (PMID: 20465995, 21707886, 33260258). This variant has been identified in 56/280818 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1296 of the ATP7B protein (p.Asp1296Asn). This variant is present in population databases (rs199821556, gnomAD 0.2%). This missense change has been observed in individual(s) with Wilson disease (PMID: 11954751, 12032531, 18424137, 21707886, 32618023). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 161207). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP7B protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2022	PP1, PP3, PP4, PM2, PM3, PS4_moderate -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21707886, 20465995, 30956230, 32248359, 25637381, 22692182, 12032531, 18424137, 11954751, 30275481) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Feb 09, 2023	PP3_STR, PM3_STR -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;.;.;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;.;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0080	D;D;D;D;D;.;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D
Vest4		0.94
MVP		0.99
MPC		0.37
ClinPred		0.44	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs199821556; hg19: chr13-52511629;