rs60431989

Positions:

• chr13-51941194-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):​c.3443T>C​(p.Ile1148Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,066 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 9.27

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 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 13-51941194-A-G is Pathogenic according to our data. Variant chr13-51941194-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37122.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.3443T>C	p.Ile1148Thr	missense_variant	16/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3443T>C	p.Ile1148Thr	missense_variant	16/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152176 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000401 AC: 10 AN: 249586 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000389

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461890 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152176 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2018	The ATP7B c.3443T>C; p.Ile1148Thr variant (rs60431989), is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Wilson disease (Dedoussis 2005, Gu 2013, Panagiotakaki 2004, Yu 2017). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 37122), and is found in the East Asian population with an allele frequency of 0.041% (8/19,538 alleles) in the Genome Aggregation Database. The isoleucine at codon 1148 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Ile1148Thr variant is considered to be pathogenic. References: Dedoussis GV et al. Wilson disease: high prevalence in a mountainous area of Crete. Ann Hum Genet. 2005 May;69(Pt 3):268-74. Gu S et al. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. PLoS One. 2013 Jul 2;8(7):e66526. Panagiotakaki E et al. Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A. 2004 Dec 1;131(2):168-73. Yu H et al. Clinical features and outcome in patients with osseomuscular type of Wilson's disease. BMC Neurol. 2017 Feb 17;17(1):34. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant replaces isoleucine with threonine at codon 1148 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). Functional studies in yeast have shown that this variant results in normal protein expression and mild to intermediate deficits in a complementation assay (PMID: 20333758). This variant has been reported in individuals affected with Wilson disease (PMID: 9801873, 10447265, 14986826, 15523622, 15845031, 17587212, 18034201, 18483695, 21796144, 21034864, 22677543, 24146181, 23843956, 23275100, 25089800, 24726229, 26580967, 27022412, 27982432, 28212618, 29930488, 30384382, 30884209, 30702195, 34470610, 34400371, 35782615) and is consider a founder variant in several Chinese populations (PMID: 23843956, 30384382). In a number of these individuals, this variant was confirmed to be in the homozygous state or compound heterozygous state (PMID: 15523622, 20465995, 24146181, 23843956, 23275100, 27982432, 28212618, 30702195). One individual carried this variant along with a variant of uncertain significance in cis and third variant known to be pathogenic in trans (PMID: 15845031). In a separate study, this variant was identified in four individuals affected with Wilson disease, all carrying the same variant of uncertain significance in cis and different known pathogenic variants in trans (PMID: 18034201). This variant has been identified in 11/280974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 10, 2018	Variant summary: ATP7B c.3443T>C (p.Ile1148Thr) results in a non-conservative amino acid change located in the ATP-loop functional domain region in the encoded protein sequence (Luoma_2010). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277638 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (4e-05 vs 5.40e-03), allowing no conclusion about variant significance. The variant, c.3443T>C, has been reported in the literature in multiple individuals affected with Wilson Disease, in trans with other pathogenic variants (Loudianos_1998, Haas_1999, Gu_2003, Abdelghaffar_2008, Mak_2008, Panagiotakaki_2004). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Luoma_2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 08, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 27, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jun 23, 2020	ACMG classification criteria: PS4, PM2, PM3, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1148 of the ATP7B protein (p.Ile1148Thr). This variant is present in population databases (rs60431989, gnomAD 0.04%). This missense change has been observed in individual(s) with Wilson disease (PMID: 21796144, 23843956, 28212618). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37122). 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 expected to disrupt ATP7B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 20333758). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 09, 2023	The p.Ile1148Thr variant in ATP7B has been reported in >10 individuals with Wilson disease, including at least 2 homozygotes and 8 compound heterozygotes (Gu 2013 PMID: 23843956, Hua 2016 PMID: 27398169, Manolaki 2009 PMID: 19172127, Yu 2017 PMID: 28212618). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 37122) and has been identified in 0.02% (1/3472) of Ashkenazi Jewish and 0.005% (2/41438) chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), which is low enough to be consistent with a recessive allele frequency for Wilson disease. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP3. -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 13, 2021	PS3, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ATP7B: PM3:Very Strong, PM2, PP4, PS3:Supporting -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2015

The p.I1148T variant (also known as c.3443T>C), located in coding exon 16 of the ATP7B gene, results from a T to C substitution at nucleotide position 3443. The isoleucine at codon 1148 is replaced by threonine, an amino acid with similar properties. In two studies, this alteration was detected in cohorts of individuals with Wilson disease (diagnoses based on clinical and biochemical symptoms) at rates of 8.7% and 9% (Mak CM, et al. J. Hum. Genet. 2008 ; 53(1):55-63, Wang LH, et al. J. Hum. Genet. 2011; 56(9):660-5). In one functional study, authors showed that this alteration did not show a loss of expression of full length protein on western blot, but they explained that the alteration is present in a b-sheet, with its functional group facing toward the nucleotide binding pocket, and may therefore affect hydrophobicity (Luoma LM, et al. Hum. Mutat. 2010;31(5):569-77). This alteration has been detected in both the heterozygous and homozygous state in several chromosomes from individuals with Wilson disease (diagnoses based on clinical and biochemical symptoms) (Gu S, et al. PLoS ONE 2013;8(7):e66526, Loudianos G, et al. Eur. J. Hum. Genet.;6(5):487-91, Dedoussis GV, et al. Ann. Hum. Genet. 2005;69(Pt 3):268-74, Panagiotakaki E, et al. Am. J. Med. Genet. A 2004;131(2):168-73, Vrabelova S, et al. Mol. Genet. Metab. ; 86(1-2):277-85, Panichareon B, et al. Eur J Med Genet ; 54(2):103-7). This variant was previously reported in the SNPDatabase as rs60431989, but was not reported in the 1000 Genomes Project or the NHLBI Exome Sequencing Project (ESP) population-based cohorts. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;.;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.4	D;D;D;D;D;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D;D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D
Vest4		0.89
MutPred		0.89		Loss of stability (P = 0.002);.;.;.;.;.;.;
MVP		0.97
MPC		0.42
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs60431989; hg19: chr13-52515330;