rs568009639

Positions:

• chr13-51939056-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000053.4(ATP7B):​c.3694A>C​(p.Thr1232Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1232I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.65

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877
• PP5: Variant 13-51939056-T-G is Pathogenic according to our data. Variant chr13-51939056-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.3694A>C	p.Thr1232Pro	missense_variant	17/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3694A>C	p.Thr1232Pro	missense_variant	17/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249572 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135406

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 26, 2020	The ATP7B c.3694A>C; p.Thr1232Pro variant (rs568009639) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with Wilson disease, and segregates with disease in at least one family (Coffey 2013, Deguti 2004, Margarit 2005, Velez-Pardo 2004). This variant is reported in ClinVar (Variation ID: 555144), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 1232 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Based on available information, this variant is considered to be likely pathogenic. References: Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. Deguti MM et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398. Margarit E et al. Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet. 2005 Jul;68(1):61-8. Velez-Pardo C et al. New mutation (T1232P) of the ATP-7B gene associated with neurologic and neuropsychiatric dominance onset of Wilson's disease in three unrelated Colombian kindred. Neurosci Lett. 2004 Sep 9;367(3):360-4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1232 of the ATP7B protein (p.Thr1232Pro). This variant is present in population databases (rs568009639, gnomAD 0.003%). This missense change has been observed in individual(s) with Wilson disease (PMID: 15024742, 15337266, 15952988). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 555144). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 17, 2023	This missense variant replaces threonine with proline at codon 1232 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 and in the compound heterozygous state in individuals affected with Wilson disease (PMID: 15024742, 15337266, 15952988, 23518715, 27992490, 33159804, 34400371, 34620762, 36096368, 36096368; DOI: 10.4172/lpma.1000228, 10.46531/sinapse/AO/210033/2021). This variant has been identified in 1/249572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D;.;.;.;.;.
Eigen	Benign	0.19
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.9	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;.;D
REVEL	Pathogenic	0.88
Sift	Benign	0.12	T;D;T;T;T;.;T
Sift4G	Benign	0.17	T;T;T;T;T;T;T
Polyphen		0.93	P;D;D;D;D;P;D
Vest4		0.59
MutPred		0.81		Loss of MoRF binding (P = 0.0534);.;.;.;.;.;.;
MVP		0.97
MPC		0.40
ClinPred		0.93	D
GERP RS		2.7
Varity_R		0.93
gMVP		0.87

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: rs568009639; hg19: chr13-52513192;