rs72552259

Variant names:

• chr13-51960274-C-T
• rs72552259
• NM_000053.4:c.1995G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_000053.4(ATP7B):​c.1995G>A​(p.Met665Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,613,894 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. M665V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (10 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:18 B:2
• Conservation: PhyloP100: 2.43

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

Our verdict: Benign. The variant received -8 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.011927754).
• BP6: Variant 13-51960274-C-T is Benign according to our data. Variant chr13-51960274-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157933.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=16, Likely_benign=2}. Variant chr13-51960274-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.1995G>A	p.Met665Ile	missense_variant	Exon 7 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.1995G>A	p.Met665Ile	missense_variant	Exon 7 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152182 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00150 AC: 374 AN: 249208 AF XY: 0.00169

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00211 AC: 3090 AN: 1461594 Hom.: 10 Cov.: 31 AF XY: 0.00221 AC XY: 1605 AN XY: 727102

Gnomad4 AFR exome AF: 0.000299 AC: 10 AN: 33472

Gnomad4 AMR exome AF: 0.000850 AC: 38 AN: 44714

Gnomad4 ASJ exome AF: 0.00628 AC: 164 AN: 26132

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00204 AC: 176 AN: 86236

Gnomad4 FIN exome AF: 0.0000187 AC: 1 AN: 53418

Gnomad4 NFE exome AF: 0.00229 AC: 2544 AN: 1111840

Gnomad4 Remaining exome AF: 0.00252 AC: 152 AN: 60370

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152300 Hom.: 2 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74458

Gnomad4 AFR AF: 0.000409 AC: 0.000409027 AN: 0.000409027

Gnomad4 AMR AF: 0.00137 AC: 0.00137255 AN: 0.00137255

Gnomad4 ASJ AF: 0.00403 AC: 0.00403458 AN: 0.00403458

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000829 AC: 0.0008285 AN: 0.0008285

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00237 AC: 0.00236695 AN: 0.00236695

Gnomad4 OTH AF: 0.000946 AC: 0.000946074 AN: 0.000946074

Alfa AF: 0.00189 Hom.: 1

Bravo AF: 0.00142

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000248 AC: 1

ESP6500EA AF: 0.00263 AC: 22

ExAC AF: 0.00132 AC: 160

EpiCase AF: 0.00213

EpiControl AF: 0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:18 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Uncertain:12 Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with isoleucine at codon 665 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in many individuals affected with Wilson disease (PMID: 9671269, 20517649, 22484412, 22677543, 23518715, 24517292, 25825851, 30232804, 32118851, 32154060, 33640437). In several of these individuals, this variant was reported in the compound heterozygous state (PMID: 23518715, 25825851, 32118851, 33640437). However, at least one individual carrying this variant in trans with a known pathogenic variant was asymptomatic (PMID: 32043565). This variant has been identified in 408/280594 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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 10, 2023

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2021

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with isoleucine at codon 665 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in many individuals affected with Wilson disease (PMID: 9671269, 20517649, 22484412, 22677543, 23518715, 24517292, 25825851, 30232804, 32118851, 32154060, 33640437). In several of these individuals, this variant was reported in the compound heterozygous state (PMID: 23518715, 25825851, 32118851, 33640437). However, at least one individual carrying this variant in trans with a known pathogenic variant was asymptomatic (PMID: 32043565). This variant has been identified in 408/280594 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. -

Oct 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.1995G>A, p.Met665Ile variant (rs72552259, ClinVar Variation ID: 157933) is reported in the literature in multiple individuals affected with Wilson disease, including in at least two individual with a pathogenic variant detected in trans (Bost 2012, Coffey 2013, Ferenci 2014, Lepori 2012, Loudianos 1998, Nilles 2023, Van Biervliet 2015, Weiss 2010). This variant is found in the general population with an overall allele frequency of 0.15% (408/280,594 alleles, including a single homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.655). Due to limited information, the clinical significance of the p.Met665Ile variant is uncertain at this time. References: Bost M et al. Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. J Trace Elem Med Biol. 2012 Jun;26(2-3):97-101. PMID: 22677543. Coffey A et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013; 136(Pt 5):1476-87. PMID: 23518715. Ferenci P. Phenotype-genotype correlations in patients with Wilson's disease. Ann N Y Acad Sci. 2014 May;1315:1-5. PMID: 24517292. Lepori MB et al. Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: contribution to diagnosis. Mol Cell Probes. 2012 Aug;26(4):147-50. PMID: 22484412. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998; 12(2):89-94. PMID: 9671269. Nilles C et al. Diagnosis and Outcomes of Late-Onset Wilson's Disease: A National Registry-Based Study. Mov Disord. 2023 Feb;38(2):321-332. PMID: 36573661. Van Biervliet S et al. Clinical zinc deficiency as early presentation of Wilson disease. J Pediatr Gastroenterol Nutr. 2015;60(4):457-9. PMID: 25825851 Weiss KH et al. Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S233-40. PMID: 20517649 -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.1995G>A(p.Met665Ile) variant in ATP7B gene has been reported in compound heterozygous state in individuals affected with Wilson disease (Tampaki M, et. al., 2020; Collins CJ, et. al., 2021; Wallace DF, et. al., 2020). This variant is present with an allele frequency of 0.1% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Likely Benign/ Likely Pathogenic/ Uncertain Significance (multiple submissions). Computational evidence (Polyphen -Benign, SIFT -Damaging and MutationTaster -disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 665 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance. -

Apr 03, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 06, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:3 Benign:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP7B: PM5, BS2 -

Jan 10, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20517649, 22677543, 9671269, 22692182, 26764160, 10447265, 22484412, 32118851, 32154060, 32248359, 30275481, 33640437, 32043565, 30097039, 34405919, 30476936, 24517292, 23518715, 25825851, 34620762, 37937776, 36573661, 39502306) -

Dec 29, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Apr 18, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATP7B c.1995G>A (p.Met665Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 1615994 control chromosomes, predominantly at a frequency of 0.006 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 12 homozygotes. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP7B causing Wilson Disease phenotype (0.0054). c.1995G>A, has been reported in the literature in multiple presumed compound heterozygous individuals affected with Wilson Disease (WD) (e.g. Coffey_2013, VanBiervliet_2015, Ferenci_2019, Tampaki_2020, Collins_2021), including at least individual who carried a pathogenic variant in trans. For many WD individuals with the variant in the literature, a second mutation is not provided (e.g., Bost_2012, Lepori_2012, Loudianos_1998, Penon-Portmann_2020, Tampaki_2020), and for those that did have a second variant phase was seldom reported (though we tallied at least 10 distinct rare or LP/P variants reported as the second allele). We could not find any significant reporting of segregation with disease for this variant. These data indicate that the variant is possibly associated with disease and may be a hypomorphic variant, but there is currently insufficient evidence to make a determination. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22677543, 23518715, 30097039, 33640437, 24517292, 30232804, 22484412, 9671269, 32154060, 32043565, 32118851, 25825851, 32248359, 38532509, 37937776, 39502306, 30275481, 10447265, 23235335, 36112267, 24253677, 20517649, 36573661, 35535697, 30476936, 31059521, 39535360, 31751128, 22692182, 34405919, 31449670, 34620762). ClinVar contains an entry for this variant (Variation ID: 157933). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Inborn genetic diseases Uncertain:1

Mar 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1995G>A (p.M665I) alteration is located in exon 7 (coding exon 7) of the ATP7B gene. This alteration results from a G to A substitution at nucleotide position 1995, causing the methionine (M) at amino acid position 665 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epileptic encephalopathy Uncertain:1

Mar 15, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;T;.;.;.
Eigen	Benign	-0.0078
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.9	L;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.4	N;N;D;.;N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.021	D;T;D;.;D
Sift4G	Benign	0.062	T;T;T;T;T
Polyphen		0.17	B;B;B;B;B
Vest4		0.39
MutPred		0.81		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);
MVP		0.93
MPC		0.066
ClinPred		0.016	T
GERP RS		4.5
Varity_R		0.38
gMVP		0.83
Mutation Taster		=73/27	disease causing (ClinVar)

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: rs72552259; hg19: chr13-52534410;